The research team drew on the TriNetX network, a federated platform that aggregates anonymised electronic health records from dozens of participating healthcare organisations across the United States, covering more than 103 million patients. From this vast pool, the investigators identified everyone aged sixteen or older who had at least one recorded body mass index of 35 kilograms per square metre or higher between January 2005 and December 2022. Patients who underwent bariatric surgery within six months of such a record formed the exposed group, while everyone with severe obesity but no record of surgery formed the comparison group.

Because observational comparisons of this kind are vulnerable to confounding, the researchers used propensity score matching to pair each surgical patient with a non-surgical patient sharing the same profile of age, sex, ethnicity, race, BMI category, hypertension, type 2 diabetes, socioeconomic circumstances, smoking, alcohol-related disorders, and a detailed history of neurological and psychiatric conditions including epilepsy, head injury, depression, schizophrenia, and family history of nervous system disease. After matching, each cohort contained 32,552 individuals, and the balance of measured confounders was verified using a standardised mean difference threshold of 0.1.

Follow-up was tracked with Cox proportional hazards regression, the standard statistical tool for estimating how an exposure changes the rate of an event over time. The median follow-up was 4.7 years in the surgery group and 5.9 years in the comparison group, with maximum observation approaching twenty years. Over that period, patients who had bariatric surgery showed a 52.4 percent lower incidence rate of dementia, corresponding to a hazard ratio of 0.48 with a 95 percent confidence interval of 0.39 to 0.58. The reduction in Parkinson’s disease was smaller but still statistically robust, at 30.1 percent, with a hazard ratio of 0.70.

When the investigators broke dementia down by subtype, the pattern became even more intriguing. Alzheimer’s disease incidence was 42.3 percent lower after surgery, while vascular dementia, the form most closely tied to impaired blood flow in the brain, fell by 73.1 percent. That pronounced vascular signal hints at one plausible mechanism: bariatric surgery is known to improve blood pressure, glycaemic control, and lipid profiles, all of which protect the small vessels that nourish neural tissue. Chronic systemic inflammation, oxidative stress, and insulin resistance, each of which is dampened by substantial weight loss, are also implicated in neuronal damage and cognitive decline.

The gut hormone story may be equally important. Procedures such as sleeve gastrectomy and Roux-en-Y gastric bypass dramatically increase postprandial secretion of glucagon-like peptide-1, or GLP-1, and peptide YY while suppressing the hunger hormone ghrelin. GLP-1 receptors are expressed in the central nervous system, and preclinical work suggests the hormone carries anti-inflammatory, antioxidant, and mitochondria-protecting effects in the brain. This biology has fuelled a wave of trials testing GLP-1-based drugs against neurodegeneration, including phase 3 studies of oral semaglutide in early Alzheimer’s disease and trials of lixisenatide and exenatide in Parkinson’s disease, with results so far mixed but suggestive enough to keep the field intensely interested.

There is also a dopamine angle. Neuroimaging studies have shown that obesity is associated with reduced availability of striatal dopamine D2/3 receptors, a change reversed by surgical weight loss. Because dopaminergic degeneration is the hallmark of Parkinson’s disease, the restoration of dopamine receptor availability after surgery offers a credible route by which the operation might lower Parkinson’s risk. Notably, the authors report that no prior study had ever examined the association between bariatric surgery and Parkinson’s disease incidence, making this the first estimate of its kind.

To gauge whether the neurological findings were credible or artefacts of real-world data, the team also measured outcomes with established links to surgery. The results aligned closely with previous literature: cardiovascular disease incidence was 46.9 percent lower, obesity-associated cancers were 34.3 percent lower, and all-cause death was 54.3 percent lower among surgical patients, whose twenty-year survival probability was 84.7 percent versus 81.8 percent in the comparison group. Reproducing these benchmark associations strengthens confidence that the dementia and Parkinson’s estimates reflect genuine biology rather than systematic bias.

The researchers did run sensitivity analyses that temper the headline claims. When outcomes recorded in the first six months after the index date were excluded to guard against detection bias, the dementia association persisted at a 47.5 percent reduction, but the Parkinson’s link lost statistical significance, and the authors caution that the relatively small number of Parkinson’s events limits statistical power and raises the possibility of chance findings. Comparing the two dominant procedures directly, Roux-en-Y gastric bypass and sleeve gastrectomy showed no meaningful difference in either neurological outcome, suggesting the benefit, if real, is shared across surgical techniques.

As with any observational study, causality cannot be established, and the authors are candid about the limitations. Selection bias, calendar-time bias, possible immortal time effects, residual confounding by factors such as education and insurance coverage, and the possibility that surgical patients simply enjoy better healthcare access all remain concerns. An earlier Utah-based study even reported increased dementia risk after surgery, potentially linked to post-operative nutritional deficiencies such as vitamin B12 and D, although that analysis suffered from notable selection and ascertainment problems. The Leicester team argues that its tighter matching and exclusion of pre-existing disease make its estimates more reliable. What the new findings ultimately offer is a provocative hypothesis, grounded in gut hormone biology and vascular physiology, that the most effective treatment for severe obesity may also shield the ageing brain, and that surgery, GLP-1 pharmacology, and neurodegeneration research are now converging on the same question.

Subject of Research: Association between bariatric surgery and the incidence of dementia and Parkinson's disease in patients with severe obesity

Article Title: Bariatric surgery and risk of dementia and Parkinson’s disease in patients with obesity

Article References: Shiekh, S. I., Papamargaritis, D., Goldney, J., Hernandes, G., Davies, M. J., Khunti, K., Yates, T., & Zaccardi, F. (2026). Bariatric surgery and risk of dementia and Parkinson’s disease in patients with obesity. International Journal of Obesity. https://doi.org/10.1038/s41366-026-02222-z

Image Credits: AI Generated

DOI: 10.1038/s41366-026-02222-z

Keywords: bariatric surgery, dementia, Parkinson's disease, obesity, GLP-1, propensity score matching, TriNetX, cardiovascular disease, weight loss, neurodegeneration, cohort study, International Journal of Obesity

The research team began with a deceptively simple question: which parts of the turnip actually matter for metabolism? Rather than testing a crude extract and stopping there, the investigators employed an activity-guided purification strategy. They ground ten kilograms of dried turnip root, extracted it with ethanol, and then partitioned the resulting material into fractions of increasing chemical refinement. Each fraction was tested in a laboratory model of insulin resistance: HepG2 liver cells bathed in high glucose and palmitic acid, a fatty acid that mimics the lipid overload seen in obesity and diabetes. The researchers measured how much glucose the cells could absorb, a direct readout of insulin sensitivity, and systematically eliminated fractions that showed no activity or toxicity.

The purification funnel narrowed dramatically. Of the two major fractions produced by liquid-liquid partitioning, the n-butanol fraction outperformed the water fraction at promoting glucose uptake. Silica gel chromatography then split this fraction into five subfractions, one of which, designated T-2D, stood out clearly. A second round of reversed-phase chromatography generated four refined subfractions, and the winner was unambiguous: T-3B drove glucose uptake in insulin-resistant hepatocytes to the highest levels observed in the entire screening campaign, reaching nearly 6.9 millimolar under the assay conditions, all without harming cell viability. This stepwise approach, the authors argue, addresses a persistent weakness in natural product research, where crude mixtures and single isolated compounds are often studied in isolation, leaving the interactions among constituents undefined.

With the active fraction in hand, the team moved to animal testing. They used db/db mice, a classic spontaneous model of type 2 diabetes in which animals carry a mutation that renders them obese, insulin resistant, and dyslipidemic. Mice with fasting blood glucose above 11.1 millimolar were randomized into groups receiving either a low dose of T-3B, a high dose, the anti-diabetic drug rosiglitazone as a positive control, or vehicle alone. Treatment was delivered by daily oral gavage for eight consecutive weeks, with body weight, food intake, and fasting glucose tracked weekly throughout.

The metabolic improvements were substantial and, in several respects, dose-dependent. High-dose T-3B lowered fasting blood glucose significantly as early as the second week of treatment, while the low dose produced significant effects by week three. Oral glucose tolerance tests performed after eight weeks showed that treated mice cleared a glucose load far more efficiently than untreated diabetic controls, with the high-dose group’s area under the glucose curve rivaling that of the rosiglitazone group. Insulin tolerance tests confirmed that the treated animals had genuinely recovered sensitivity to the hormone, not merely altered some downstream glucose metric. Body weight and food intake also declined moderately in treated mice, beginning around the sixth week of intervention.

Blood chemistry added another layer of benefit. Circulating levels of glucagon-like peptide-1, or GLP-1, an incretin hormone secreted by intestinal cells that promotes insulin release and satiety, were markedly depressed in the untreated diabetic mice but substantially restored by T-3B treatment. The fraction also corrected the characteristic diabetic lipid profile: plasma triglycerides, total cholesterol, and low-density lipoprotein all fell at the high dose, while high-density lipoprotein rose at both doses tested. Because elevated triglycerides and LDL cholesterol contribute to atherosclerotic risk in diabetic patients, the authors note that this dual glucose-and-lipid effect is exactly the profile sought in next-generation metabolic therapies, and one that many existing drugs only partially achieve.

The liver emerged as the fraction’s primary target organ. Histological staining revealed that untreated db/db mice livers were riddled with fat droplets, with ballooned hepatocytes and disordered tissue architecture, hallmarks of non-alcoholic fatty liver disease. T-3B treatment visibly reversed this steatosis, and biochemical assays confirmed reduced hepatic triglyceride content. Intriguingly, hepatic glycogen, the storage form of glucose, increased significantly in treated mice, while skeletal muscle glycogen remained unchanged, sharpening the picture of a liver-specific mechanism. The researchers propose that this matters because hepatic insulin resistance is an early and central driver of type 2 diabetes: when the liver stops responding to insulin, it churns out glucose uncontrollably while simultaneously importing fatty acids that worsen fat accumulation, creating a self-reinforcing vicious cycle between lipid deposition and metabolic dysfunction.

Molecular and genomic analyses converged on two well-known signaling hubs. Western blotting showed that diabetic mouse livers had blunted phosphorylation of the insulin receptor beta, insulin receptor substrate 1, AKT, and AMPK alpha, the canonical cascade through which insulin instructs the liver to store glucose and cease glucose production. Eight weeks of T-3B treatment rescued these phosphorylation defects in a dose-dependent manner, and parallel experiments in insulin-resistant HepG2 cells reproduced the effect within twenty-four hours. RNA sequencing of liver tissue reinforced the story at the transcriptomic level: more than 1,600 genes changed expression after treatment, with downregulated genes enriched in inflammatory pathways such as NF-kappaB and TNF signaling, oxidative stress responses, and cellular senescence, while upregulated genes clustered in fatty acid oxidation, the PPAR pathway, glycogen biosynthesis, and AMPK signaling itself.

Chemical fingerprinting of T-3B by high-performance liquid chromatography coupled with mass spectrometry and nuclear magnetic resonance identified six monomeric constituents: trans-4-hydroxycinnamic acid, chrysin, ferulic acid, trans-ferulic acid, 4-hydroxy-3,5-dimethoxycinnamic acid, and apigenin. When each was tested individually in insulin-resistant liver cells at twenty micromolar, chrysin and apigenin proved the strongest promoters of glucose uptake, with chrysin the single most potent compound despite not being the most abundant. Combining chrysin and apigenin produced an enhanced effect beyond simple addition, which the authors attribute to their shared flavone backbone and complementary regulatory pathways. Chrysin alone also reduced triglyceride and cholesterol accumulation in fat-injured liver cells, lowered markers of cellular damage, boosted the antioxidant enzyme superoxide dismutase, and reduced malondialdehyde, a marker of oxidative injury.

The authors are careful to flag the limits of their work. The reduced food intake observed in treated mice could partly confound the metabolic benefits, and the team acknowledges that pair-fed control groups would be needed to fully disentangle direct drug effects from dietary restriction. The signaling findings, while consistent, remain correlative without inhibitor or gene-knockdown experiments, the transcriptomic results await validation by quantitative PCR, and the absolute quantities and purity of the individual monomers were not fully quantified. The mechanism behind the restored GLP-1 secretion, whether direct stimulation of intestinal cells, gut signaling, or microbiome remodeling, also remains speculative. Still, the study delivers something the field has lacked: a defined, purified turnip fraction with a mapped component-pathway-phenotype network connecting specific flavones to insulin and energy-sensing signaling in the liver. As diabetes prevalence in China now exceeds twelve percent, well above the global average, and drug side effects push patients toward dietary alternatives, the prospect that a common vegetable harbors multi-target metabolic activity is a finding worth watching closely.

Subject of Research: Bioactive turnip compounds as potential treatments for type 2 diabetes and hepatic insulin resistance

Article Title: Bioactive components from Turnip improve liver and systemic metabolic homeostasis in mice with T2DM

Article References: Ling, Z., Jin, L., Xu, W., Sun, M., Sun, J., Zhou, Z., Liu, Q., Wang, Y., Liu, J., Wu, J., Khattab, O. M., Fu, H., Shou, Q., & Han, J. (2026). Bioactive components from Turnip improve liver and systemic metabolic homeostasis in mice with T2DM. Journal of Agriculture and Food Research, 31, Article 103344. https://doi.org/10.1016/j.jafr.2026.103344

Image Credits: AI Generated

DOI: Not provided

Keywords: turnip, type 2 diabetes, chrysin, apigenin, insulin resistance, liver metabolism, db/db mice, AMPK, PI3K-AKT, flavonoids, GLP-1, fatty liver disease

The experimental system was built on Caco-2 cells, a workhorse of gastrointestinal research. When grown under the right conditions, these human colorectal cancer cells differentiate into a monolayer that behaves remarkably like the lining of the small intestine, complete with absorptive properties, tight junctions between neighboring cells, and even the capacity to secrete enteroendocrine hormones. That makes them an ideal first-pass model for asking whether a botanical extract can influence the biology of the gut wall before any animal or human work is attempted. The team, led by Heggar Venkataramana Sudeep, first established a safety window using an MTT cytotoxicity assay, testing concentrations of the extract ranging from 25 to 500 micrograms per milliliter. Only concentrations that left the cells unharmed were carried forward, ensuring that any molecular changes observed were genuine regulatory effects rather than signs of cellular distress.

The headline finding concerns the GLP-1 system itself. After 24 hours of treatment, the highest non-toxic dose, 100 micrograms per milliliter, drove a 3.33-fold increase in the expression of the Proglucagon gene, the blueprint from which GLP-1 is manufactured, and a 3.32-fold rise in the gene encoding the GLP-1 receptor, the molecular dock that receives the hormone’s signal. Both changes were statistically robust, with the Proglucagon effect reaching a significance threshold of p less than 0.001. The paired upregulation is significant because it suggests the extract is not merely prompting cells to produce more hormone but also priming the signaling apparatus that responds to it, a combination the authors interpret as stimulation of endogenous GLP-1 signaling rather than a one-dimensional hormonal push.

Producing more GLP-1 is only half the battle, because the hormone is famously short-lived. An enzyme called dipeptidyl peptidase-4, or DPP-4, slices incretin hormones into inactive fragments within minutes of their release, which is precisely why a class of diabetes drugs called DPP-4 inhibitors exists to prolong GLP-1’s working life. The extract appeared to attack this problem from two directions. In the Caco-2 cells, Leanskolin significantly reduced both the activity of cellular DPP-4 and the expression of the gene that encodes it, compared with untreated controls. In a separate cell-free enzyme assay, the extract inhibited DPP-4 directly, with a half-maximal inhibitory concentration, or IC50, of 262.5 micrograms per milliliter. That potency is modest compared with synthetic pharmaceutical inhibitors, but the dual mechanism, suppressing the enzyme’s production while also dampening its activity, hints at a layered strategy for extending the bioavailability of the hormone the cells are producing in greater quantities.

Perhaps the most intriguing piece of the puzzle involves bitter taste receptors. It is now well established that the gut is not a passive tube but a sensory organ, studded with the same TAS2R bitter receptors found on the tongue. When these receptors detect bitter compounds, they can trigger cascades that influence appetite, hormone release, and gut motility. In the study, Leanskolin modulated the expression of three bitter receptor genes, TAS2R38, TAS2R43, and TAS2R14, in a concentration-dependent manner with statistical significance at p less than 0.05. The authors suggest this points to a role in nutrient sensing and enteroendocrine signaling, raising the possibility that forskolin or companion compounds in the extract act as bitter agonists that help coax the gut’s hormone-producing cells into action. If confirmed, this would place the extract in a growing family of bitter-tasting botanicals being investigated as natural modulators of gut hormone release.

The second major axis of the study concerned the physical integrity of the intestinal barrier. A healthy gut wall is a selectively permeable gatekeeper, held together by tight junction proteins that seal the gaps between epithelial cells. When that seal loosens, a condition sometimes called leaky gut, bacterial fragments and other unwanted molecules can slip into the bloodstream, fueling the low-grade inflammation that is increasingly implicated in obesity, insulin resistance, and metabolic syndrome. The researchers assessed barrier function using two complementary readouts. Transepithelial electrical resistance, or TEER, measures how well the cell monolayer resists the passage of ions, while FITC-flux assays track the movement of a fluorescent marker across the layer, a proxy for paracellular leakiness.

The results here were nuanced but encouraging. Treatment with the extract at concentrations from 25 to 100 micrograms per milliliter for 24 hours did not change TEER values, suggesting the overall ionic tightness of the monolayer was preserved rather than perturbed. However, FITC-flux dropped significantly at the 50 and 100 microgram doses, with p values below 0.01, indicating that the passage of larger molecules through the paracellular route was reduced. Consistent with that functional improvement, the extract enhanced the expression of tight junction proteins, the molecular rivets of the barrier, at p less than 0.05 compared with controls. In other words, the barrier was not merely being stressed into tightening; the cells appeared to be actively building more of the structural proteins that hold the wall together.

Taken together, the authors frame the extract as a multi-target agent for metabolic health, simultaneously activating GLP-1 pathway genes, curbing the enzyme that degrades GLP-1, engaging the sensory receptors that regulate enteroendocrine responses, and reinforcing the gut’s physical defenses. That combination matters because these processes are biologically intertwined. GLP-1 released from intestinal L-cells slows gastric emptying, promotes satiety, and enhances glucose-dependent insulin secretion, while a robust epithelial barrier limits the inflammatory signals that can drive insulin resistance. A single intervention that touches both sides of that equation is unusual, particularly one derived from a plant whose active constituent has been on the market for decades.

Caution is warranted before anyone reaches for a forskolin supplement expecting a natural Ozempic. This was a cell culture study, and the concentrations used, up to 100 micrograms per milliliter applied directly to cells in a dish, do not translate straightforwardly into human doses or blood levels. Caco-2 cells, though useful, are a cancer-derived model that only approximates real intestinal physiology, and gene expression changes do not guarantee meaningful hormone secretion in a living body. There is also a disclosure worth noting: all of the authors are employed by Vidya Herbs Pvt. Ltd., the company behind the Leanskolin ingredient, and the paper explicitly declares this potential conflict of interest. Independent replication in animal models and eventually controlled human trials will be essential to determine whether the effects survive the journey from dish to person.

Even with those caveats, the study opens a genuinely novel research direction. Forskolin has historically been studied for its ability to activate adenylate cyclase and raise intracellular cyclic AMP, a signaling molecule with wide-reaching effects, and it is tempting to speculate that this canonical mechanism could underlie some of the observed gene expression changes. But the breadth of the effects, spanning incretin genes, DPP-4, bitter receptors, and tight junction proteins, suggests the standardized extract may act through converging pathways rather than a single switch. As interest in gut-derived hormones reshapes metabolic medicine, the idea that a well-characterized botanical extract could engage the same biology, however gently, is likely to keep this line of investigation moving from the culture flask toward the clinic.

Subject of Research: Effects of a standardized Coleus forskohlii extract on GLP-1 signaling and intestinal barrier integrity in Caco-2 cells

Article Title: Targeting GLP-1 signaling and barrier integrity with Leanskolin™, a standardized Coleus forskohlii extract: a Caco-2 cell-based study for metabolic health support

Article References: Sudeep, H. V., Kumara, T. P. P., Lingaraju, H. B., & Shyamprasad, K. (2026). Targeting GLP-1 signaling and barrier integrity with Leanskolin™, a standardized Coleus forskohlii extract: a Caco-2 cell-based study for metabolic health support. BMC Complementary Medicine and Therapies. https://doi.org/10.1186/s12906-026-05590-1

Image Credits: AI Generated

DOI: 10.1186/s12906-026-05590-1

Keywords: GLP-1, forskolin, Coleus forskohlii, Caco-2 cells, DPP-4 inhibition, gut barrier, tight junctions, incretin hormones, metabolic health, bitter taste receptors, natural products, enteroendocrine signaling

The finding matters because gestational diabetes affects a substantial share of pregnancies worldwide and raises risks for both mother and child, including future type 2 diabetes. Previous observational work had already hinted that pregnant women who develop the condition tend to have lower levels of butyrate in their circulation. What remained unclear was whether this deficiency was merely a byproduct of the disease or a genuine driver of it, and if the latter, through which molecular route butyrate might act. The new study set out to answer both questions with a combination of human data, animal experiments and mechanistic work at the level of chromatin.

The clinical arm of the study was a nested case-control analysis that measured serum butyrate and active GLP-1, the glucagon-like peptide-1 hormone released by intestinal cells after meals to stimulate insulin secretion, in pregnant women. The results were striking in their consistency: women who went on to develop gestational diabetes had significantly lower levels of both butyrate and active GLP-1, and this difference was detectable not only in mid-pregnancy, when the condition typically manifests, but already in early pregnancy. That early timing is important, because it suggests that a depleted butyrate-GLP-1 axis precedes the onset of disease rather than simply following from it, raising the possibility of prediction and even prevention.

To test causality, the team turned to a mouse model of gestational diabetes induced by a high-fat diet combined with antibiotics, a regimen that disrupts the gut microbial community and mimics the metabolic disturbances seen in patients. When the animals received a probiotic supplement of Clostridium butyricum, a bacterium renowned for its butyrate production, their metabolic picture improved markedly. Hyperglycaemia eased, insulin resistance declined, and perhaps most intriguingly, the disruption of circadian glucose rhythms that accompanies gestational diabetes was partially corrected. Microbial profiling of the treated animals confirmed that the supplement enriched the community of butyrate-producing bacteria and raised systemic butyrate levels, tying the metabolic benefits directly to the microbial metabolite.

The mechanistic heart of the study lies in the colon. Butyrate has long been known to act as an inhibitor of histone deacetylases, enzymes that remove acetyl groups from histone proteins and, in doing so, keep stretches of DNA tightly packed and transcriptionally silent. When the researchers examined colon tissue from the treated mice, they found that Clostridium butyricum supplementation reduced the abundance of one particular deacetylase, HDAC3, and increased the global acetylation of histone H3 at lysine 27, a chemical mark known as H3K27ac that flags active genes and their regulatory elements. In other words, the microbial metabolite appeared to be physically opening up the genome in intestinal cells.

Which genes were being opened? To find out, the team performed integrated RNA sequencing and H3K27ac chromatin immunoprecipitation sequencing in enteroendocrine cells, the hormone-producing specialists of the gut lining, treated with sodium butyrate and with agents that modulate HDAC3. The multi-omics analysis converged on a single compelling candidate: secretagogin, or SCGN, a calcium-binding protein expressed in enteroendocrine cells. Butyrate enhanced both the transcription of SCGN and the deposition of H3K27ac at its promoter, indicating that the metabolite directly activates the gene through the same epigenetic mechanism. Because SCGN has been implicated in the regulated secretion of peptide hormones, the connection to GLP-1 was an obvious next step.

The functional experiments confirmed it. Treating enteroendocrine cells with butyrate, or knocking down HDAC3 with molecular tools, increased SCGN expression and boosted the secretion of GLP-1. Conversely, when the researchers forced cells to overexpress HDAC3, the SCGN-GLP-1 axis was suppressed, but this suppression could be reversed by co-treatment with butyrate. The epigenetic brake and the microbial metabolite were locked in a push-pull relationship: HDAC3 silences the hormone-secreting programme, and butyrate releases it. This is a textbook example of how a dietary and microbial signal can be translated into a durable change in gene expression, one that ultimately shapes whole-body metabolism.

Genetic validation in living animals provided the final, decisive test. The team used mice that carry only one functional copy of the HDAC3 gene, a condition known as haploinsufficiency, which reduces the protein’s levels without eliminating it entirely. If the benefits of Clostridium butyricum truly flow through HDAC3 inhibition, then animals with less HDAC3 to begin with should gain little from the probiotic. That is precisely what the researchers observed: in HDAC3-haploinsufficient mice, the metabolic improvements and the upregulation of SCGN driven by the bacterium were abolished. The genetic experiment closes the causal loop and rules out the possibility that butyrate works through unrelated pathways.

Taken together, the study delineates what the authors describe as a novel gut microbiota-epigenetic-hormonal axis. Gut bacteria produce butyrate; butyrate inhibits HDAC3 in the intestinal lining; HDAC3 inhibition raises H3K27ac at the SCGN promoter; SCGN activation potentiates GLP-1 secretion; and GLP-1 improves glucose homeostasis for mother and fetus. Each link in this chain was tested independently, from the human correlation through the mouse intervention to the chromatin-level biochemistry and the genetic knockout. The architecture of the pathway is elegant precisely because it is specific: rather than a diffuse anti-inflammatory effect, the metabolite acts on a defined enzyme at a defined genomic target to produce a defined hormonal outcome.

The translational implications are considerable. HDAC3 and the downstream SCGN-GLP-1 pathway now stand as candidate targets for preventing or treating gestational diabetes, whether through probiotic supplementation with butyrate-producing strains such as Clostridium butyricum, dietary strategies that favour butyrate-producing communities, or future drugs that modulate HDAC3 activity in the gut. The authors note that their work was supported by the Beijing Municipal Natural Science Foundation, the National Natural Science Foundation of China and related programmes, and the study was conducted under ethics approvals for both the human cohort and the animal experiments. As with any mouse study, the road to clinical application will require trials in pregnant women, but the early-pregnancy signature of low butyrate and low GLP-1 offers a tantalising window for intervention long before the disease declares itself. For a condition that shapes the lifelong metabolic health of two generations at once, a microbial molecule that rewrites gene expression in the gut may prove to be one of the most consequential discoveries in pregnancy metabolism in years.

Subject of Research: How the gut microbial metabolite butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis

Article Title: The gut microbiota-derived butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis

Article References: Han, W., Zhang, Y., Huang, J., Lu, Y., Yin, X., Zhao, Y., Yuan, X., Yang, R., Zhang, L., Zheng, W., & Li, G. (2026). The gut microbiota-derived butyrate improves gestational glucose homeostasis through HDAC3 inhibition and epigenetic activation of the SCGN/GLP-1 axis. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-08720-y

Image Credits: AI Generated

DOI: 10.1186/s12967-026-08720-y

Keywords: gestational diabetes, butyrate, gut microbiota, HDAC3, epigenetics, GLP-1, secretagogin, Clostridium butyricum, histone acetylation, H3K27ac, enteroendocrine cells, insulin resistance

The work, published in the Journal of Eating Disorders, emerges from the Norwegian Microbiota Study in Anorexia Nervosa, known as NORMA, a project funded by the Norwegian Research Council that examines how gut biology and eating disorders intersect. The team, led by Ida Heir Hovland and Siv Kjølsrud Bøhn of the Norwegian University of Life Sciences together with collaborators at Oslo University Hospital and other Norwegian centers, and including eating disorders researcher Cynthia M. Bulik of the Karolinska Institutet and the University of North Carolina at Chapel Hill, enrolled 42 patients with anorexia nervosa admitted for inpatient treatment and 42 age-matched healthy controls. Blood samples were drawn from patients at baseline, after six weeks, and after twelve weeks of treatment, while the healthy controls provided a single baseline sample for comparison.

The analytical approach was deliberately broad. Using Luminex technology, a bead-based immunoassay platform that can quantify many proteins simultaneously in a small volume of serum, the researchers measured an array of hormones and signaling molecules central to appetite regulation: ghrelin, the stomach-derived hormone that stirs hunger; leptin, the fat-cell hormone that signals long-term energy stores; insulin and C-peptide, markers of pancreatic insulin secretion; adipsin and resistin, adipose-derived factors; adiponectin, another fat-cell hormone with metabolic and anti-inflammatory roles; the incretin hormones GLP-1 and GIP, which are released by the gut after eating and modulate insulin secretion and satiety; glucagon; plasminogen activator inhibitor-1; and visfatin. Dietary intake was captured with a three-day digital food diary and interview, allowing the team to connect hormone levels not just to weight but to what patients actually ate.

The baseline differences were striking. Compared with healthy controls, patients with anorexia nervosa showed significantly lower levels of adipsin, leptin, insulin, and resistin, and significantly higher levels of adiponectin and glucose-dependent insulinotropic polypeptide, or GIP. Ghrelin, the hunger hormone, was also elevated in patients, though the difference fell just short of statistical significance with a p-value of 0.08. No baseline differences emerged for C-peptide, plasminogen activator inhibitor-1, or visfatin. Intriguingly, the size of the group difference in GLP-1 and glucagon depended on age, with discrepancies between patients and controls being greater in older participants, a hint that the hormonal signature of the illness may shift across the lifespan.

These patterns make physiological sense in the context of severe starvation. Leptin is produced by adipose tissue in proportion to fat stores, so its near-absence in emaciated patients is expected. Low insulin reflects reduced nutrient intake and reduced body fat. Elevated ghrelin is the body’s classic cry for food. But the elevated adiponectin and GIP are less intuitive, and their persistence raises questions about whether the gut–brain axis in anorexia nervosa is merely responding to starvation or has been fundamentally rewired by it. Adiponectin typically rises as fat mass falls, yet its other roles in inflammation and energy metabolism suggest it may be doing more than simply tracking body composition.

Then came treatment. Over twelve weeks of structured inpatient care, designed around nutritional rehabilitation, the patients’ mean body mass index rose significantly from 15.5 to 18.2 kilograms per square meter, a substantial gain that nonetheless left most patients below the healthy BMI range. The hormonal response to this refeeding was a study in partial recovery. Adipsin, leptin, insulin, and C-peptide all increased, moving in the direction of healthy control values. Ghrelin decreased and approached the levels seen in controls. In other words, the hormones most tightly coupled to fat mass and acute nutrient flux responded to treatment much as one would predict from basic endocrinology.

But four signals stood apart. Glucagon, adiponectin, GIP, and GLP-1 were largely resistant to change across the twelve weeks of treatment. These are precisely the hormones most entangled with the gut side of the gut–brain axis: GLP-1 and GIP are secreted by intestinal enteroendocrine cells in response to food, and glucagon, produced by the pancreatic alpha cells, governs glucose mobilization during fasting. Their stubbornness suggests that refeeding and weight gain, at least over this timeframe, are not sufficient to normalize every arm of the appetite-signaling network. The authors interpret this as evidence of continued gut–brain axis dysregulation, a molecular echo of the illness that persists even as the body is refed.

Perhaps the most consequential finding of the study concerns diet. When the researchers examined associations between the biomarkers and what patients ate, they found that body mass index alone did not fully account for the hormonal differences between patients and controls. Dietary composition, particularly the intake of fiber and fat, appeared to matter independently for hormone regulation in anorexia nervosa. This is a technically important observation because it implies that the quality and macronutrient profile of the diet, not merely the total energy delivered, may shape how the appetite-signaling system recovers. Fiber is well known to influence gut hormone secretion through fermentation by the gut microbiota, producing short-chain fatty acids that stimulate enteroendocrine L-cells, the very cells that produce GLP-1. Fat intake, meanwhile, influences both incretin release and the absorption kinetics of meals. The NORMA study’s microbiota focus makes this connection especially tantalizing, since the gut bacteria that ferment fiber are themselves altered in anorexia nervosa.

The clinical implications are considerable but deliberately framed as open questions by the authors. Nutritional treatment is a cornerstone of anorexia nervosa care, and weight restoration remains essential, yet the persistence of abnormal levels of glucagon, adiponectin, GIP, and GLP-1 after twelve weeks of intensive treatment suggests that weight gain alone may not fully repair the biological machinery of appetite. Whether these unresponsive hormones can be targeted through tailored nutritional strategies, such as manipulating fiber or fat intake, or through pharmacological therapies aimed at the gut–brain axis, remains to be investigated. The GLP-1 system is already a major drug target in obesity and diabetes, and understanding why it behaves anomalously in anorexia nervosa could open new therapeutic avenues for a disorder where restoring the drive to eat is the central clinical challenge.

The study’s design carries caveats that the authors acknowledge through its framing as exploratory. With 42 patients and 42 controls, the sample is modest, and the healthy controls were only measured once, limiting the ability to model within-person change in that group. Twelve weeks is a short window in the arc of recovery from an illness that often runs a chronic course, and the patients’ BMIs at the end of treatment were still below the healthy range, so it remains possible that some hormones would normalize with further weight restoration. Still, the trial was prospectively registered with ClinicalTrials.gov under identifier NCT06144905, and the longitudinal sampling within treatment gives the findings a temporal texture that cross-sectional studies cannot match. What emerges is a picture of anorexia nervosa as not only a psychological disorder of eating but a systemic endocrine condition, one in which the molecular conversation between gut and brain is disrupted at baseline, partially restored by refeeding, and in key respects strikingly resistant to change. For clinicians and researchers alike, the message is that the scale tells only part of the story, and that the hormones of hunger may hold the rest.

Subject of Research: Appetite-related biomarker changes during inpatient treatment of anorexia nervosa and their association with diet and body mass index

Article Title: Exploring appetite-related biomarkers in anorexia nervosa during treatment: associations with diet and comparison with healthy controls

Article References: Hovland, I. H., Otterdal, K. L., Bang, L., Vinje, H., Herfindal, A. M., Strømland, S. S., Aspholm, T. E., Arsenovic, D., Reistad, H. T., Dahl, J., Ones, M. L., Weider, S., Bulik, C. M., Rø, Ø., & Bøhn, S. K. (2026). Exploring appetite-related biomarkers in anorexia nervosa during treatment: associations with diet and comparison with healthy controls. Journal of Eating Disorders. https://doi.org/10.1186/s40337-026-01752-1

Image Credits: AI Generated

DOI: 10.1186/s40337-026-01752-1

Keywords: anorexia nervosa, appetite hormones, gut-brain axis, ghrelin, leptin, GLP-1, GIP, adiponectin, dietary fiber, nutritional rehabilitation, biomarkers, eating disorders

The study, led by Tracy Tylka, a professor of clinical psychology at Ohio State’s Marion campus, together with co-author Nichole Wood-Barcalow, a psychologist in private practice in Westerville, Ohio, introduces and validates the first trait-based measurement tool designed specifically to capture what the authors call self-oriented appearance comparison. The instrument, named the Self-Oriented Comparison Scale for Appearance, or SOCS-A, is an 11-item measure that was tested across two separate community samples of U.S. adults to confirm its psychometric accuracy. Its very existence fills a conspicuous void. As Tylka noted, there is an enormous literature on social comparison in the body image and eating disorder fields, and virtually nothing on comparisons people make with their own past selves. Established scales measuring comparison to others are used routinely in both research and clinical practice, yet when Tylka searched for an equivalent trait-based scale for self-oriented comparison, she found that none had ever been developed.

The origin of the project was clinical rather than theoretical. Wood-Barcalow, Tylka’s former graduate student, kept encountering the same pattern among her clients: people who would pore over old photographs and videos, measuring their current appearance against how they looked years earlier, often with visible distress. They would tell her things like, “Oh my gosh, I can’t believe how much I’ve changed.” These reflections were frequently triggered by major life milestones and physical transitions — puberty, pregnancy, menopause, andropause, illness, aging, and weight fluctuations. While some clients felt they had changed for the better, most perceived these appearance-related shifts negatively. The observation suggested a psychological phenomenon that was common, consequential, and almost entirely unmeasured by the field’s existing instruments.

Statistical analysis of the new scale revealed something structurally interesting: self-oriented comparison is not a single, uniform behavior. Instead, the data supported two distinct subscales, mirroring the upward and downward distinction long recognized in social comparison research. Upward self-oriented comparison involves measuring your current reflection against a past vision of yourself in which you felt more attractive — the younger, leaner, smoother-skinned self enshrined in a wedding photo or a college snapshot. Downward self-oriented comparison means looking back at a photo, memory, or period when you felt less attractive than you do now. The two directions, it turns out, carry profoundly different psychological consequences.

Among study participants, upward self-oriented comparison was strongly linked to negative body image, body shame, rumination, and disordered eating. Downward comparison, by contrast, was associated with lower levels of shame and with higher appearance pride and body appreciation. This asymmetry surprised the researchers. In the social comparison literature, downward comparison — measuring yourself against others you perceive as less attractive — tends to be maladaptive, linked to body-focused shame, guilt, and reduced body image flexibility. Tylka had expected a similar pattern here. Instead, the data pointed the other way. Her interpretation offers a compelling explanation: when we compare ourselves unfavorably to others, we may feel guilt or discomfort about the comparison itself, or pity for the other person. But when we look back at a past self we did not like and see how far we have come, the comparison often reflects effort and change we accomplished ourselves. It is a record of overcoming something, and it yields pride and a sense of accomplishment rather than shame.

The study also uncovered gender differences in how these comparisons operate. The scale functioned the same way structurally across the gender spectrum, meaning its underlying measurement properties held for all participants. But the scores themselves diverged: women scored considerably higher than men on upward self-oriented comparison, while men scored higher on downward self-oriented comparison. Tylka connects this pattern to societal pressures that weight appearance differently across genders. Women are expected to maintain a certain appearance, and deviations from that ideal tend to trouble them more because their social worth is often tied to how they look. Men, by contrast, may more often experience their appearance history as a trajectory of improvement or at least of change they directed, making downward comparisons — looking back at a less satisfying past self — more available and more benign.

One of the study’s most pointed critiques concerns who has historically been studied. Tylka notes that body image and eating disorder research has long focused on young white women or adolescents, populations whose comparisons tend to be oriented toward others rather than toward their own pasts. The body image field, she argues, has been late to recognize ageism and the near-absence of research on the aging process as it relates to body image. As people age, they move further away from what society tells them they should look like, and the natural reference point shifts inward — toward photographs, videos, and memories from decades ago. A measurement tool built for adolescents comparing themselves to their peers is poorly suited to a sixty-year-old woman confronting a photograph of her thirty-year-old face. The SOCS-A is designed to close that gap, and Tylka hopes it will be translated and adopted by research teams around the world to explore the experiences of diverse groups undergoing appearance-related changes.

The clinical implications may be the study’s most immediate contribution. Tylka argues that the findings should change how therapists approach clients struggling to adjust to appearance-related changes, including aging. Treatment has traditionally focused on how clients compare themselves to others; the new evidence suggests practitioners should also attend to how clients compare themselves to previous versions of themselves, because self-oriented comparison is uniquely associated with body image and eating behavior in ways that social comparison alone does not capture. The scale could be deployed in prevention programs, clinical interventions, and therapy settings, and researchers could use it to evaluate whether upward self-oriented comparison actually decreases as a result of treatment — turning a newly named construct into a measurable treatment target.

Tylka also sees relevance well beyond aging. She points to the growing use of GLP-1 medications, the class of drugs that has transformed treatment for obesity and diabetes and, in doing so, produced rapid and dramatic changes in millions of people’s bodies. She is beginning research with colleagues on GLP-1 use, body image, and eating behavior; the data have not yet been analyzed, but she anticipates that the intersection with self-oriented comparison will be revealing. People whose bodies change quickly, whether through medication, illness, pregnancy, or aging, are precisely the people most likely to stand before a mirror and compare what they see now with what they remember. If upward self-oriented comparison proves to be a driver of distress in these populations, the SOCS-A could help clinicians identify and address it early.

What the study ultimately offers is a reframing. The mirror has always had two audiences: the world outside, and the self that existed before. Decades of research have mapped the harms of the first comparison with precision, building scales, models, and interventions around it. The second comparison went largely unnamed, even as clients in therapy rooms described it over and over — the shock of old photographs, the grief for a younger body, the quiet pride of having changed on one’s own terms. By naming the phenomenon, distinguishing its upward and downward forms, and providing a validated instrument to measure it, the Ohio State team has given researchers and clinicians a way to ask a question the field had overlooked: not just how do you measure up to others, but how do you measure up to the person you used to be? The answer, the evidence now suggests, shapes body image and eating behavior in ways that are real, measurable, and — for many people — more intimate and more painful than any comparison with a stranger. The work was funded by an Ohio State Joan Huber Fellowship Grant.

Subject of Research: Development and validation of the Self-Oriented Comparison Scale for Appearance to measure comparisons with one's past self and their effects on body image and eating behavior

Article Title: The risk of looking back at former versions of ourselves

Article References: The risk of looking back at former versions of ourselves. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: body image, self-oriented comparison, SOCS-A, social comparison, eating disorders, aging, psychometrics, Ohio State University, body shame, gender differences, GLP-1, clinical psychology

FXR, the farnesoid X receptor, is expressed predominantly in the liver, intestine, and kidneys, and functions as the body’s principal bile acid sensor. Its endogenous ligands are bile acids themselves, with binding potency following a clear hierarchy: chenodeoxycholic acid is the strongest activator, followed by deoxycholic acid, lithocholic acid, and finally cholic acid. Once activated, FXR operates a sophisticated transcriptional network that keeps bile acid levels in check. In the liver, it ramps up production of the small heterodimer partner, a transcriptional repressor that shuts down CYP7A1 and CYP8B1, the two enzymes that drive bile acid synthesis. In the intestine, FXR triggers the release of fibroblast growth factor 15 in rodents and 19 in humans, which travels through the portal vein to the liver and binds the FGFR4 receptor complex to suppress bile acid production through a second, independent route. The review emphasizes that this dual feedback system is most powerful in the liver, with weaker but meaningful effects in the small intestine and kidneys.

Beyond bile acid chemistry, FXR acts as a metabolic conductor. Activation of the receptor suppresses SREBP-1c, the master switch for fatty acid and triglyceride synthesis, through SHP-dependent signaling, while simultaneously boosting PPARα activity to upregulate carnitine palmitoyl transferase 1 and accelerate fat burning through beta-oxidation. FXR also reshapes the fatty acid profile of the liver, lowering both monounsaturated and polyunsaturated fatty acid levels through distinct mechanisms. Its influence extends to glucose: protein kinase A-mediated phosphorylation of FXR activates gluconeogenic gene expression, while intestinal FXR stimulates secretion of glucagon-like peptide-1, the incretin hormone made famous by blockbuster diabetes and obesity drugs, thereby promoting insulin release and improving glucose tolerance. The receptor additionally damps inflammation by suppressing NF-κB signaling, reducing interleukin-6 and interleukin-1β, and by directly blocking the assembly of the NLRP3 inflammasome through SHP, preventing caspase-1 activation and the pyroptotic cell death that fuels hepatic inflammation.

The clinical implications of these mechanisms are enormous. In cholestatic liver diseases such as primary biliary cholangitis and primary sclerosing cholangitis, where toxic bile acids accumulate and destroy tissue, FXR agonists have been the leading therapeutic strategy for years. Obeticholic acid, a derivative of chenodeoxycholic acid, became the first approved FXR agonist for primary biliary cholangitis in 2016 and showed promise in metabolic dysfunction-associated steatohepatitis as well. Yet the review delivers a striking update: amid persistent safety concerns and disappointing results in the COBALT trial, the manufacturer voluntarily withdrew obeticholic acid from the United States market in September 2025. Hepatotoxicity, severe pruritus, and unfavorable lipid changes had outweighed its benefits. The withdrawal casts a long shadow over the field and underscores why newer agents such as cilofexor, tropifexor, and vonafexor—each designed for better selectivity and tolerability—remain in various stages of clinical development, some already halted for lack of efficacy and others still advancing.

In fatty liver disease, the review describes FXR as a reliable intervention point operating through multiple converging pathways. The receptor inhibits fat production via the FXR-SHP-SREBP1c axis, promotes fat oxidation through PPARα, and induces detoxification enzymes such as CYP3A4 and sulfotransferase 2A1 to enhance bile acid clearance. Intriguingly, FXR also participates in a reciprocal positive feedback loop with SIRT1, the longevity-associated histone deacetylase: FXR induces SHP, which suppresses microRNA-34a and thereby lifts the brake on SIRT1 expression, while SIRT1 in turn deacetylates FXR, stabilizing it and promoting its nuclear translocation. Intestinal FXR adds another layer of protection by maintaining epithelial tight junctions, preserving the gut vascular barrier through Wnt/beta-catenin signaling, and upregulating antimicrobial defenses. In liver cancer, the evidence is equally compelling. Mice lacking FXR spontaneously develop hepatocellular carcinoma with bile acid accumulation and elevated beta-catenin target genes, and FXR activation directly disrupts the beta-catenin-TCF4 transcriptional complex while also suppressing tumor progression through the JAK2-STAT3 pathway and the FGF15/19-FGFR4 axis.

TGR5, the review’s second protagonist, tells a complementary story through entirely different cell biology. Rather than sitting in the nucleus, TGR5 is embedded in the plasma membrane, where bile acid binding triggers cyclic AMP production within seconds. It is distributed widely across the liver, gallbladder, intestine, kidney, spleen, brain, skeletal muscle, and brown adipose tissue, with ligand potency ranking lithocholic acid highest, followed by deoxycholic acid, chenodeoxycholic acid, and cholic acid. In metabolic terms, TGR5 activation promotes GLP-1 secretion from intestinal endocrine cells, enhances insulin sensitivity, and induces the browning of white adipose tissue. The review details two thermogenic mechanisms: cAMP-PKA signaling enhances the conversion of thyroid hormone T4 to the active T3, upregulating uncoupling protein 1 and driving mitochondrial heat production, while a parallel pathway induces mitochondrial creatine kinase 2 to establish a UCP1-independent futile creatine cycle. Together these actions increase energy expenditure and counteract obesity.

TGR5 also functions as an immunological brake. Its activation inhibits NF-κB and NLRP3 inflammasome signaling through the cAMP-PKA axis, steering macrophages away from the pro-inflammatory M1 phenotype and toward the reparative M2 state. In models of cholestasis induced by bile duct ligation, TGR5 knockout worsened oxidative stress and Kupffer cell polarization, while TGR5 agonists reduced damage by inhibiting NF-κB and activating the Nrf2/HO-1 pathway. In cancer, TGR5-deficient mice proved more susceptible to chemically induced liver cancer, and receptor activation suppressed tumor development through STAT3 inhibition. Agonist development, however, remains early: the semi-synthetic bile acid analog INT-777 has never entered human trials, while the next-generation candidate RDX8940 shows potent activity against insulin resistance and hepatic steatosis in preclinical models but still lacks human safety data. Antagonists such as SBI-115 and SBI-364, meanwhile, have revealed unexpected value in polycystic kidney and liver disease, where excessive TGR5 signaling drives aberrant bile duct proliferation.

Perhaps the review’s most important contribution is its portrait of FXR and TGR5 as an interlocking system rather than two isolated targets. The two receptors coordinate bile acid homeostasis, with FXR providing the slow transcriptional feedback and TGR5 handling rapid metabolic responses. Along the gut-liver axis, bile acids activate FXR in enterocytes to release FGF15/19 while simultaneously engaging TGR5 on intestinal L cells to secrete GLP-1, and gut microbes remodel bile acid structures into conjugates that can activate both receptors at once. During liver regeneration, knockout of either receptor delays recovery, indicating partial functional compensation that is not fully interchangeable. In the intestinal epithelium the two receptors actually pull in opposite directions—FXR restrains proliferation through cell-cycle inhibitors like p21 while TGR5 promotes it through cAMP-PKA and EGFR crosstalk—creating a delicate balance that maintains tissue homeostasis.

The review closes with a candid assessment of the obstacles ahead. Only a small fraction of FXR- and TGR5-targeted drugs have reached clinical use, and most candidates suffer from low bioavailability, short duration of action, or side effects such as pruritus, dyslipidemia, and hepatotoxicity. FXR biology is strikingly tissue-dependent: only about 11 percent of FXR binding sites are shared between mouse liver and intestine, and while single-organ knockout produces mild phenotypes, double knockout causes severe cholestatic injury, revealing that hepatic and intestinal FXR cannot substitute for one another. TGR5’s role in primary sclerosing cholangitis remains genuinely contested, with evidence both for cholangiocyte-protective and disease-promoting functions depending on context. The authors call for deeper mechanistic mapping of cell-type-specific receptor functions, next-generation dual-target modulators, combination strategies with GLP-1 receptor agonists, and rigorously designed trials. For a field still reeling from obeticholic acid’s withdrawal, the message is clear: bile acid receptors remain among the most promising targets in hepatology, but realizing that promise will require matching the elegance of the biology with equally sophisticated pharmacology.

Subject of Research: The roles of the bile acid receptors FXR and TGR5 in hepatic steatosis, fibrosis, cholestatic disease, and hepatocellular carcinoma

Article Title: The Bile Acid Signaling Axis: Deciphering the Roles of FXR and TGR5 in Hepatic Steatosis, Fibrosis, and Cancer

Article References: Liu, J., Sun, K., Liu, H., Zhu, M., Li, C., He, Y., & Qin, L. (2026). The Bile Acid Signaling Axis: Deciphering the Roles of FXR and TGR5 in Hepatic Steatosis, Fibrosis, and Cancer. Pharmacology Research & Perspectives, 14(5), Article e70318. https://doi.org/10.1002/prp2.70318

Image Credits: AI Generated

DOI: 10.1002/prp2.70318

Keywords: bile acids, FXR, TGR5, liver fibrosis, hepatocellular carcinoma, MASLD, MASH, cholestasis, obeticholic acid, GLP-1, NF-kB, gut-liver axis

Incretins occupy a central position in the entero-insular axis, the signalling network by which the gut primes the pancreas to release insulin after a meal in a glucose-dependent manner. GLP-1, a 30-amino-acid polypeptide secreted by L cells of the terminal ileum and colon, binds a G protein-coupled receptor distributed across pancreatic islets, adipose tissue, the cardiovascular system, the central nervous system and, crucially, the reproductive organs. Its classical action involves activation of the cAMP/PKA cascade in pancreatic beta cells, enhancing insulin gene transcription and glucose-dependent insulin secretion. The hormone also regulates voltage-dependent calcium channels to promote calcium influx, suppresses glucagon release from alpha cells, and engages the PI3K pathway to sharpen peripheral insulin sensitivity.

The molecular picture has grown considerably richer in recent years. Researchers identified the adipokine zinc-alpha2-glycoprotein as a possible mediator of the metabolic benefits of GLP-1 receptor agonists, with twelve weeks of liraglutide treatment significantly elevating circulating ZAG levels in patients with type 2 diabetes. Other teams have explored ways to boost the body’s own GLP-1 output: the dietary compound imperatorin and glycyrrhizic acid, a principal component of licorice, both activate the TGR5 receptor to enhance GLP-1 secretion in experimental models. Even receptor architecture is proving malleable—bioluminescence resonance energy transfer studies revealed that the GLP-1 receptor can form heterodimers with the secretin receptor in islet cells, altering calcium signalling and inducing cross-desensitisation between the two receptors.

GIP, the second major incretin, is a 42-amino-acid peptide produced by K cells in the duodenum and jejunum. Though less intensively studied than GLP-1, it promotes insulin biosynthesis, supports beta-cell differentiation and survival, and enhances fat storage and bone formation. Work by Samms and colleagues showed that GIP enhances lipoprotein lipase activity in adipocytes through a PI3K/PKB-LKB1/AMPK-TORC2 signalling axis, promoting lipid uptake and storage while increasing insulin sensitivity. Intriguingly, GIP and GLP-1 signalling appear intertwined: N-glycosylation-deficient GIP receptors can be functionally rescued by co-expression with wild-type GLP-1 receptors, hinting at functional heterodimerisation between the two receptor classes.

The most clinically mature application in gynaecology is polycystic ovary syndrome, a condition characterised by hyperandrogenemia and insulin resistance that affects a growing number of women worldwide. Studies have confirmed abnormal secretion of both GIP and GLP-1 in patients with PCOS, and clinical research has shown that GLP-1 receptor agonists such as liraglutide and semaglutide can improve menstrual regularity, raise ovulation rates and reduce body fat. Mechanistically, the agonist exenatide was found to improve insulin resistance in PCOS rats by activating the AMPKalpha-SIRT1 pathway, while GLP-1 receptor agonists more broadly bolster antioxidant defences via the Nrf2/ARE pathway and reduce endoplasmic reticulum stress through modulation of the PERK pathway.

Genetic evidence adds weight to the GIP connection. A two-sample Mendelian randomisation analysis found that genetic activation of the GIP receptor is associated with a reduced risk of PCOS, and animal work shows that GIP signalling regulates the oestrous cycle and female fertility through the pituitary-gonadal axis. The gut microbiome may also be a critical link: dysbiosis in PCOS elevates the microbial metabolite agmatine, which activates the farnesoid X receptor and suppresses GLP-1 secretion from intestinal L cells, contributing to insulin resistance and ovarian dysfunction. This agmatine-FXR-GLP-1 axis offers a compelling explanation for how gut health, metabolism and reproduction converge in the syndrome.

Beyond the ovary, incretins display striking anti-inflammatory and anti-fibrotic properties with direct relevance to uterine disease. GLP-1 suppresses macrophage inflammatory factors including IL-1beta, IL-6 and TNF-alpha, and gene therapy studies in obese diabetic mice showed reduced macrophage infiltration of adipose tissue and inhibition of NF-kappaB and JNK signalling. In models of intrauterine adhesion, semaglutide alleviated fibrosis and inflammation by modulating NF-kappaB and reducing fibrotic markers such as ACTA2, COL1A1 and FN, while dulaglutide improved endometrial thickness and reduced collagen deposition by suppressing M1 macrophage polarisation and the TGF-beta/Smad2 pathway. Preclinical studies likewise suggest GLP-1 receptor agonists can inhibit the proliferation of ectopic endometrial cells in endometriosis through PI3K/Akt and NF-kappaB pathways.

The anti-tumour signals are tantalising but preliminary. In endometrial cancer cell lines, liraglutide inhibited proliferation in a time- and concentration-dependent manner, activating AMPK, upregulating progesterone receptors and synergising with medroxyprogesterone acetate. Autophagy appears central: liraglutide induced autophagic cell death by increasing LC3 expression and p-AMPKalpha while decreasing SQSTM1. For ovarian cancer, GLP-1 receptor expression has been documented in some tumour tissues, and agonists can curb proliferation and invasion via AMPK in vitro—but the authors are careful to stress that these anti-tumour effects may be partly secondary to weight loss and improved metabolic status, and direct effects require clinical validation.

Perhaps the most conceptually ambitious frontier is the brain-gut axis. Incretins directly modulate the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes, and electrophysiological recordings show GLP-1 acting on GnRH neurons to increase firing rates and GABAergic synaptic input. GLP-1 receptor agonists may increase pulsatile GnRH release via the hypothalamic kisspeptin system, influencing luteinising hormone secretion, while peripherally promoting follicular development and oocyte maturation through effects on theca cells. GIP receptor knockout mice exhibit disrupted oestrous cycles and reduced fertility, underscoring GIP’s non-redundant role. Notably, a dual GLP-1/oestrogen agonist improved ovarian cyclicity and insulin sensitivity in PCOS mouse models without direct estrogenic proliferative effects on the uterus.

Clinical translation, however, demands caution. Combination therapy with metformin outperforms metformin alone for weight, BMI and insulin sensitivity, and semaglutide reduced lingual fat in women with PCOS in a randomised trial—yet adverse events are more frequent with combination regimens, and real-world data show 17.8% of patients are non-responders to semaglutide or liraglutide for obesity. Gastrointestinal symptoms remain the most common side effects, and safety concerns persist regarding gallbladder disorders, pancreatitis and rodent C-cell findings. Use in pregnancy and lactation is not recommended, with regulators advising contraception and a two-month washout before conception. For endometriosis, intrauterine adhesions and gynaecological cancers, the evidence remains almost entirely preclinical. The authors call for large, multicentre randomised trials with reproductive outcomes as primary endpoints, dedicated exploration of dual GIP/GLP-1 agonists such as tirzepatide, and tissue-specific studies to disentangle direct hormonal actions from the indirect fruits of metabolic improvement. Incretin-based therapy, they conclude, represents a promising interdisciplinary bridge between endocrinology and gynaecology—one whose full span has yet to be built.

Subject of Research: The role and mechanisms of the incretin hormones GLP-1 and GIP in gynaecological diseases

Article Title: The Role and Mechanism of Incretins in Gynaecologic Diseases

Article References: Yan, J., Cao, M., Ding, Y., Zhang, Y., Sun, Y., Jiang, G., Zhang, Y., Kang, L., Zhou, X., Luo, J., & Li, B. (2026). The Role and Mechanism of Incretins in Gynaecologic Diseases. Endocrinology, Diabetes & Metabolism, 9(5), Article e70340. https://doi.org/10.1002/edm2.70340

Image Credits: AI Generated

DOI: 10.1002/edm2.70340

Keywords: incretins, GLP-1, GIP, polycystic ovary syndrome, endometrial cancer, endometriosis, intrauterine adhesions, insulin resistance, brain-gut axis, GLP-1 receptor agonists, semaglutide, women's health

The rationale for the experiment rests on how differently the two drug classes act. Incretin-based therapies such as semaglutide and tirzepatide mimic gut-derived hormones that slow gastric emptying, enhance insulin secretion and signal to brainstem and hypothalamic circuits that suppress appetite. Amylin-based agents such as cagrilintide act on a distinct receptor complex, the amylin receptor formed by AM-LNR in combination with the calcitonin receptor CALCR, and appear to reduce food intake through partly separable neural pathways. Retatrutide, the most advanced triple agonist in clinical development, adds glucagon receptor activity, which in preclinical models is associated with increased energy expenditure and favorable effects on lipid metabolism. The Copenhagen group reasoned that engaging all five receptors at once might capture complementary benefits that no single molecule, however sophisticated, could deliver.

To test this, the researchers used diet-induced obese male rats, a standard preclinical model in which animals become obese after prolonged exposure to a high-fat diet. Animals received daily subcutaneous injections of cagrilintide, retatrutide, the two drugs co-administered, or comparator regimens built around semaglutide and tirzepatide at matched doses. The results were striking: co-administration of cagrilintide and retatrutide produced dose-dependent reductions in body weight and food intake that surpassed both equimolar monotherapies and matched-dose combinations incorporating the established incretin drugs. Across multiple studies, the combination also reduced fat-pad masses and improved circulating markers of metabolic health, including total cholesterol, triglycerides and insulin, without evidence of the liver enzyme elevations that can signal hepatic stress.

A central question in obesity pharmacology is whether a drug simply makes animals eat less or whether it does something more. The team addressed this with pair-feeding and weight-matching experiments, designs in which control animals are given either the same amount of food as treated animals or are calorie-restricted until their body weight matches that of drug-treated animals. These experiments revealed that the enhanced weight loss seen with the combination could not be explained by reduced food intake alone. In other words, even when caloric intake was held constant, the cagrilintide-retatrutide pairing drove greater reductions in body weight than calorie restriction by itself, pointing to additional mechanisms, potentially involving energy expenditure, nutrient partitioning or the glucagon receptor’s effects on lipid handling.

The study went beyond physiology into molecular territory. Using advanced mass spectrometry workflows, including enrichment of extracellular vesicles from plasma, the researchers profiled the circulating proteome of treated animals. Plasma proteomic analysis showed that the combination therapy was associated with enrichment of proteins involved in bioenergetic processes, a signature consistent with altered fuel metabolism rather than mere caloric deprivation. By comparing drug-treated animals with weight-matched calorie-restricted controls, the team could separate molecular changes that simply track weight loss from those that are drug-specific, an analytical distinction they argue is essential for interpreting the biology of next-generation anti-obesity therapies.

The brain was the other major focus. Obesity drugs act centrally, and the specific neuronal programs they engage determine both their efficacy and their side-effect profile. The researchers performed bulk RNA sequencing of two key brain regions: the hypothalamus, the master hub of energy homeostasis, and the dorsal vagal complex in the brainstem, a critical relay for visceral sensory information and a major site of action for GLP-1-based drugs. Brain transcriptomic profiling revealed convergent central neuronal programs linked to energy balance regulation, and importantly, the combination therapy elicited stronger responses in hypothalamic and dorsal vagal complex gene modules than either monotherapy. The team used co-expression network analysis and cell-type enrichment mapping to connect these transcriptional signatures to specific neuronal populations, and found that modules activated by the combination were enriched for genes previously associated with human body mass index in genome-wide association studies.

These molecular findings carry practical implications for drug design. The field is currently racing to develop unimolecular multi-receptor agonists, single peptides engineered to bind several receptors at once, exemplified by retatrutide itself and by amycretin, a GLP-1 and amylin receptor co-agonist that has shown promising results in early clinical trials. The Copenhagen study suggests a blueprint for such molecules: a next-generation single agent that combines GLP-1, GIP, glucagon and amylin receptor activity in one backbone could, in principle, reproduce the pharmacology of the cagrilintide-retatrutide pair without requiring two separate injections. The authors frame their preclinical data as direct guidance for the design of these next-generation unimolecular agonists, identifying which receptor combinations and dose ratios appear most productive.

The clinical context makes the findings timely. Retatrutide has delivered powerful weight loss in a pivotal phase 3 obesity trial, and co-administered cagrilintide and semaglutide, marketed as a fixed-dose combination, has already demonstrated substantial efficacy in adults with overweight or obesity. Yet a persistent challenge remains in achieving maximal weight loss and metabolic control, particularly for patients living with both obesity and type 2 diabetes. The Copenhagen study suggests that adding amylin receptor agonism on top of a triple incretin agonist may push efficacy further than simply optimizing incretin pharmacology alone. The researchers also probed tolerability signals, including conditioned taste aversion tests in lean rats, which are used as a proxy for nausea-like aversive effects, and found dose-dependent responses that will inform how such combinations might be titrated in future studies.

Important caveats apply. All of the efficacy data come from male rats, and sex differences in response to obesity pharmacotherapy are well documented, so replication in female animals and eventually in humans will be essential. The doses used in rodents also cannot be translated directly to the clinic, and combination therapy raises questions about tolerability, cost and dosing complexity that only human trials can resolve. Nonetheless, the study provides one of the most comprehensive preclinical characterizations to date of what happens when the incretin and amylin systems are engaged simultaneously, integrating behavioral, metabolic, proteomic and transcriptomic readouts within a single experimental framework. The underlying data, including proteomic datasets deposited in the PRIDE repository and gene expression data in ArrayExpress, along with all analysis code released on GitHub, have been made openly available to the research community.

As obesity medicines evolve from single-hormone mimics toward rationally designed polypharmacology, the Copenhagen results make a compelling case that the amylin system is the most promising partner for the incretin drugs that have already transformed the field. If the five-receptor strategy translates from rats to humans, the ceiling on pharmacologically achievable weight loss, long constrained by the limits of GLP-1 receptor agonism, may be considerably higher than anyone dared to project just a few years ago.

Subject of Research: Combination therapy with cagrilintide and retatrutide for enhanced weight loss and metabolic outcomes in obese rats

Article Title: Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats

Article References: Petersen, J., Merrild, C., Holm, S. K., Kurgan, N., Hassan, S., Mathiesen, C. V., Börchers, S., Svendsen, C., D’Anna, S., Andersen, N. R., Klein, A. B., Fritzen, A. M., Deshmukh, A. S., Pers, T. H., & Clemmensen, C. (2026). Cagrilintide and retatrutide combination therapy enhances weight loss and metabolic outcomes in obese male rats. Nature Metabolism. https://doi.org/10.1038/s42255-026-01603-y

Image Credits: AI Generated

DOI: 10.1038/s42255-026-01603-y

Keywords: cagrilintide, retatrutide, obesity, GLP-1 receptor agonist, amylin, glucagon receptor, GIP, weight loss pharmacotherapy, Nature Metabolism, multi-receptor agonist, metabolic health, preclinical study

The starting point of the commentary is a deceptively simple set of numbers. Beta cells proliferate slowly compared with most other cell types. In rodents, the replication rate ranges from roughly one to two percent per day. In humans it is an order of magnitude lower, somewhere between 0.1 and 0.2 percent per day. The rate is higher in children and adolescents than in adults, because during physical growth the beta-cell mass must expand in parallel with increasing body mass to meet the rising demand for insulin. Once adulthood is reached, however, the proliferative machinery is dialed down to a near-idle pace.

That near-idle pace is not, in itself, a design flaw. During the neonatal phase and early childhood, the formation of new beta cells from progenitor cells plays a central role in expanding the beta-cell mass. In adulthood, by contrast, new beta cells arise almost exclusively through the self-duplication of existing ones. Although this rate is very low, it is not zero, and crucially it appears to be sufficient. The trickle of new cells compensates for losses caused by apoptotic beta-cell death, thereby maintaining a stable functional population across decades of life. Beta cells, in other words, retain a degree of plasticity even in the mature pancreas, but that plasticity operates within narrow limits.

Lenzen emphasizes that the organism appears to possess an internal set point for functional beta-cell mass, and that this set point serves a protective purpose. Insulin is a potentially lethal molecule when present in excess, and unregulated expansion of the beta-cell population would risk fatal hypoglycemia. The clearest demonstration of the dangers of losing this regulatory control is persistent hyperinsulinemic hypoglycemia of infancy, a congenital disorder in which the genetically determined regulation of functional beta-cell mass fails, leading to life-threatening overproduction of insulin. Far from being a limitation to be overcome, the slow proliferation rate reflects an evolved compromise between metabolic safety and repair capacity.

The set point is not fixed in stone, however. Beta-cell mass is subject to complex hormonal regulation that operates across the mammalian kingdom, including in humans. Thyroid hormones reduce beta-cell mass by promoting apoptosis, while glucocorticoids increase it by stimulating proliferation. The well-documented expansion of beta-cell mass during pregnancy provides another striking example of physiologically orchestrated adaptation. In each case, the endocrine system adjusts the size of the insulin-producing cell pool to match anticipated metabolic demand, and understanding these regulatory levers has become a central goal of diabetes research.

The relevance to disease becomes apparent when one traces what happens to beta-cell mass over a lifetime in the context of modern lifestyles. In many adults, beta-cell mass increases by up to 50 percent between the third and fifth decades of life, coinciding with the development of obesity during this period. This expansion is driven by increasing insulin resistance associated with a Western diet and lifestyle, and the accompanying rise in insulin production. Only a minority of individuals, no more than 20 percent, are able to maintain this elevated beta-cell mass and the resulting adequate insulin supply into old age despite ongoing obesity. The vast majority cannot. In most people, a gradual decline in beta-cell mass follows this phase of life, leading to insulin deficiency and ultimately to the development of type 2 diabetes. The proliferative capacity of beta cells therefore matters in two ways: it can counteract the deterioration of metabolic state during the pre-diabetic phase, and it may support efforts to restore metabolic control after diabetes onset. At the same time, any increased workload on beta cells, whether caused by obesity or autoimmune attack, carries the risk of deteriorating beta-cell function and shrinking beta-cell mass, so reducing that workload is itself a therapeutic priority.

Hormones capable of increasing beta-cell mass have consequently moved to the forefront of scientific interest, and none more so than the gut hormone glucagon-like peptide-1, or GLP-1. A recent study by Erbasan and colleagues, published in the same journal, has provided compelling new evidence for the regenerative potential of this incretin hormone. Using gene therapy in neonatal and adult streptozotocin-diabetic rats, the researchers achieved GLP-1 release through lentivirally mediated overexpression of the hormone in hepatocytes. The result was support for pancreatic beta-cell regeneration, but with a crucial developmental twist. In the neonatal pancreas, plasticity was high, and beta-cell neogenesis from progenitor and duct-derived cells was evident. In the adult pancreas, new beta cells were generated mainly through self-duplication of existing cells, confirming earlier landmark observations, with only limited potential for neogenesis and consequently for recovery of beta-cell mass.

The implications for therapy are direct. GLP-1-based treatment represents a future option for counteracting the insulin deficiency that develops gradually during the course of type 2 diabetes as beta cells progressively fail. Ideally, Lenzen argues, such intervention should occur before metabolic deterioration sets in, when supporting endogenous proliferation can preserve beta-cell mass most effectively. Treatment with a GLP-1 analogue would offer a double benefit in this window: it would support the preservation of beta-cell mass while simultaneously promoting weight loss, thereby easing the insulin resistance that drives the excessive workload on the remaining cells in the first place.

Type 1 diabetes presents an even more formidable challenge, because the beta-cell loss is driven by autoimmune destruction rather than metabolic overload. More than 90 percent of patients who develop type 1 diabetes have no family history of the disease, which means almost all individuals are diagnosed only when they manifest overt disease at stage 3, by which point much of the beta-cell mass has already been destroyed. Interestingly, however, in the weeks following disease onset, most patients enter a remission phase while receiving insulin replacement therapy, during which the remaining beta cells recover. It is during this phase, ideally after beta-cell recovery but before the onset of renewed metabolic deterioration, that the chances of achieving a significant increase in beta-cell mass through self-duplication are optimal. Seizing this window requires therapies with curative potential, and because numerous monotherapies have proven ineffective, only combination therapies based on a profound understanding of the underlying pathomechanisms and validated in reliable preclinical animal studies are considered promising candidates. A critical constraint is that successful combination therapies for type 1 diabetes require the presence of at least 30 percent of normal beta-cell mass at the start of treatment.

The arithmetic of regeneration underscores why timing is everything. Based on generally accepted beta-cell proliferation rates of one percent per day in rats and 0.1 percent per day in humans, Lenzen calculates that after a cessation of autoimmune-mediated beta-cell destruction, approximately two months are required in rats to increase beta-cell mass from one-third to two-thirds of the original healthy mass, a prediction that aligns with experimental results from animal models. By analogy, the same increase in humans would take one to two years. Encouragingly, a recent medical case study found that a combination of the two therapeutic antibodies teplizumab and adalimumab proved effective in patients, resulting in sustained metabolic health one year after the start of therapy, with no symptoms of diabetes and no need for insulin replacement. Yet the sequencing matters profoundly. Only after successfully suppressing the autoimmune destruction driven by the proinflammatory cytokines TNF-alpha and IL-1 beta, and eliminating the immune-cell infiltration within the islets, does the administration of an agent such as a GLP-1 analogue become a viable option to enhance spontaneous beta-cell regeneration. This approach is particularly suitable when beta-cell mass is already significantly reduced below 50 percent, as it provides supplementary support for proliferation. Administering the agent earlier, while the autoimmune attack is still ongoing, would merely result in the immediate destruction of the newly formed beta cells; studies in animal models have shown that during an ongoing autoimmune attack, proliferation does attempt to counteract beta-cell loss but ultimately fails.

The overarching message is one of calibrated optimism. Despite the different pathomechanisms responsible for beta-cell loss in type 1 and type 2 diabetes, distinct windows of opportunity exist for therapeutic interventions at appropriate stages of both diseases. In type 2 diabetes, that window opens in the pre-diabetic phase, when GLP-1-based therapy can preserve and support an expanded beta-cell mass before it collapses under the combined burdens of insulin resistance and age-related proliferative decline. In type 1 diabetes, the window opens after autoimmune destruction has been halted and the remaining beta cells have begun to recover, when regenerative support can rebuild a functional cell population from the residual base. In both cases, the prospect of supporting endogenous mechanisms for increasing beta-cell mass through beta-cytotrophic molecules offers a pathway that works with the body’s own biology rather than against it. The slow pace of beta-cell renewal, once viewed primarily as an obstacle, is now understood as the defining constraint that any curative strategy must respect, and the therapies that succeed will be those that arrive at precisely the right moment in the disease course.

Subject of Research: Regulation of pancreatic beta-cell mass and its implications for antidiabetic therapies

Article Title: Regulation of pancreatic beta-cell mass and its importance for antidiabetic therapies

Article References: Regulation of pancreatic beta-cell mass and its importance for antidiabetic therapies. (n.d.). https://doi.org/10.1007/s00109-026-02716-3

Image Credits: AI Generated

DOI: 10.1007/s00109-026-02716-3

Keywords: pancreatic beta cells, beta-cell mass, diabetes, type 1 diabetes, type 2 diabetes, GLP-1, beta-cell proliferation, insulin, autoimmunity, gene therapy, teplizumab, endocrinology