Brown adipose tissue, or BAT, is often described as the body’s biological furnace. Unlike white adipose tissue, which stores energy in the form of large lipid droplets, brown fat burns energy to generate heat, a process known as thermogenesis. This is accomplished largely through uncoupling protein 1, or UCP1, which short-circuits the mitochondrial proton gradient to release energy as heat rather than storing it as ATP. In humans, BAT activity declines with age and obesity, and reduced BAT function has been linked to impaired postprandial glucose clearance, meaning the body’s ability to handle blood sugar spikes after meals. This connection has fueled interest in BAT activation as a therapeutic target for metabolic disease.

The Zagreb team, led by Nikola Habek and Aleksandra Dugandžić, focused on uroguanylin, a peptide hormone that binds to guanylate cyclase C receptors and has previously been implicated in appetite regulation and gut-brain signaling. Uroguanylin is synthesized as an inactive precursor, proguanylin-like pro-uroguanylin (proUGN), which is then cleaved into its active form. While UGN’s role in the intestine is well characterized, its expression and function within the central nervous system, particularly in relation to thermoregulation, have remained poorly understood. The researchers set out to determine whether brain-derived UGN contributes to the regulation of BAT activity, and whether this contribution differs between the sexes.

To address this question, the team employed a multi-pronged experimental strategy. Brown adipose tissue activity was assessed using infrared thermography in wild-type C57Bl/6NCrl mice and UGN knockout littermates. BAT volume was measured using magnetic resonance imaging, while molecular markers associated with the “browning” of fat tissue were quantified using quantitative polymerase chain reaction. In parallel, the researchers measured proUGN expression in both mouse and human brain tissue using enzyme-linked immunosorbent assay, or ELISA. The inclusion of human tissue added a translational dimension often missing from preclinical metabolic studies.

One of the most striking findings emerged from the human brain analysis. In tissue obtained from human subjects, the researchers observed decreased proUGN expression in several brain regions, specifically the hypothalamus, Brodmann area 10, and Brodmann area 11, but only in male subjects with obesity. No comparable decrease was detected in female brain tissue. The hypothalamus is a well-established hub for autonomic control of BAT thermogenesis, receiving input from hunger and satiety circuits and sending sympathetic signals to brown fat depots via the spinal intermediolateral cell column. Brodmann areas 10 and 11, located in the prefrontal cortex, have been implicated in higher-order regulation of appetite and metabolic control. The male-specific reduction in proUGN in these regions suggests that obesity may disrupt a UGN-dependent pathway in a sexually dimorphic manner.

In mice, the relationship between feeding, brain UGN, and brown fat activation also proved to be sex-dependent. After a meal, brown adipose tissue normally increases its activity as part of diet-induced thermogenesis, helping to dissipate excess energy and support glucose disposal. The researchers found that this postprandial activation of BAT was linked to changes in hypothalamic proUGN expression, but this coupling was observed only in male mice. Female mice did not show the same pattern of hypothalamic proUGN regulation after eating, suggesting that the mechanism linking food intake to BAT activation through brain UGN operates differently, or possibly not at all, in females.

The role of the reproductive cycle added another layer of complexity. In female mice, the effects of centrally applied uroguanylin depended not only on sex but also on the phase of the estrous cycle. This finding is notable because it underscores a methodological concern that has gained increasing attention in neuroscience and metabolic research. Many laboratory studies, particularly those in rodents, historically used only male animals, partly to avoid variability attributed to the estrous cycle. The current study suggests that such variability is not mere noise but reflects genuine physiological regulation that could be clinically relevant for female patients.

The researchers also explored whether a GLP-1 analogue, a class of drugs that has transformed the treatment landscape for obesity and type 2 diabetes through medications such as semaglutide and liraglutide, could modulate brain UGN expression and BAT activity. In young male mice, intranasal administration of a GLP-1 analogue increased brown adipose tissue activity and decreased hypothalamic proUGN expression, but these effects were seen only in males. In both male and female mice, the GLP-1 analogue increased BAT activity, suggesting that GLP-1 receptor agonists engage thermogenic pathways through mechanisms that extend beyond UGN signaling, particularly in females. This observation points toward a completely different mechanism of GLP-1 action in the female brain and may help explain sex-dependent differences in clinical responses to these medications.

Chronic administration of uroguanylin itself produced another intriguing sex difference. When UGN was given repeatedly, postprandial BAT activation increased in both sexes, indicating that the hormone can indeed enhance brown fat thermogenic responses in males and females alike. However, an increase in total brown adipose tissue volume was observed only in male mice. Because BAT volume is a determinant of overall thermogenic and glucose-handling capacity, this finding implies that the long-term metabolic benefits of UGN-based interventions may be structurally different in males and females. In males, UGN appears capable of both activating existing brown fat and expanding the tissue itself, whereas in females, the effect appears limited to functional activation without tissue expansion.

The authors emphasize that the therapeutic implications of these findings are substantial. If brain-derived UGN regulates brown fat in a sex-dependent manner, then any attempt to harness this pathway for the treatment of obesity or type 2 diabetes must account for the patient’s sex. A UGN-based therapy that works well in men might produce blunted or entirely different effects in women, and vice versa. Similarly, the estrous-cycle dependence of UGN’s central effects in females raises the possibility that hormonal status, including menstrual cycle phase, hormonal contraceptive use, or menopause, could influence how women respond to BAT-targeting therapies. This kind of nuance has been historically overlooked in metabolic drug development, where clinical trials often enroll predominantly male participants or fail to stratify results by sex.

The study also raises fundamental questions about the biology of uroguanylin in the central nervous system. The finding that proUGN expression decreases in the hypothalamus and prefrontal cortex of men with obesity suggests that obesity may perturb a brain peptide system that is not typically considered part of the metabolic disease landscape. Whether this reduction is a cause or consequence of obesity, and whether it can be reversed through weight loss or pharmacological intervention, remains to be determined. The mouse data indicating that GLP-1 analogues can modulate hypothalamic proUGN expression adds an additional dimension, suggesting that some of the metabolic benefits of these blockbuster weight-loss drugs could be mediated, at least in part, through UGN-dependent pathways in males.

The Zagreb team’s work fits within a growing body of literature highlighting sex differences in metabolic physiology. Brown adipose tissue itself is known to differ between males and females in humans, with some studies suggesting higher BAT prevalence and activity in women. The neural circuits governing BAT thermogenesis, including hypothalamic and brainstem pathways, are also influenced by gonadal hormones such as estrogen and testosterone. By demonstrating that a specific brain peptide, uroguanylin, participates in this sexual dimorphism, the study provides a concrete molecular handle on a phenomenon that has long been recognized but poorly understood at the mechanistic level.

Looking ahead, the researchers suggest that the development of therapies targeting brain-activated brown fat must incorporate sex as a biological variable from the earliest stages of research and development. As the global burden of obesity and type 2 diabetes continues to grow, and as GLP-1 receptor agonists reshape expectations for pharmacological treatment, understanding the precise neural mechanisms through which these interventions work, and how they differ between men and women, will be critical for optimizing their use. The study by Habek, Ratko, Dugandžić, and colleagues represents an important step in that direction, revealing that one of the brain’s most overlooked peptides may play a central role in determining how our bodies burn the calories we consume.

Metabolic surgery, including procedures such as gastric bypass and sleeve gastrectomy, is well known to induce rapid and sustained weight loss alongside remarkable improvements in glucose homeostasis. Historically, these benefits were attributed primarily to mechanical restriction of food intake or malabsorption of nutrients. However, emerging evidence emphasizes an intricate neuroendocrine rewiring that transcends mere anatomical alterations. In this context, Blasi explores how metabolic surgery acts as a multifaceted catalyst, reshaping the gut-brain axis — a bi-directional communication network integrating metabolic signals and central nervous system control over energy balance.

One of the pivotal insights from Blasi’s analysis is the role of vagal afferent fibers (VAFs), the neural pathways that convey sensory information from the gastrointestinal tract to the brainstem. These fibers are not passive conduits; rather, they integrate complex signals from gut hormones, nutrients, and mechanical stimuli to regulate appetite, satiety, and glucose metabolism. Surgery-induced alterations modulate these afferents’ functionality, which contributes significantly to the metabolic improvements observed clinically. The review suggests that understanding these changes at a molecular and electrophysiological level may unlock novel therapeutic targets.

Delving deeper, the modulation of NMDA (N-methyl-D-aspartate) receptor subunits situated on vagal afferent neurons emerges as a promising target. NMDA receptors, critical for synaptic plasticity and signal transduction, exhibit diverse subunit compositions that influence neuronal excitability and transmission fidelity. Blasi posits that selective targeting of specific NMDA receptor subunits could mimic the neural rewiring effects of metabolic surgery. This reflects a fundamental shift from viewing surgery as a mechanical intervention to conceptualizing it as a modulatory therapy at the neurochemical level.

The intricate crosstalk between gut hormones such as GLP-1 (glucagon-like peptide-1), PYY (peptide YY), and oxyntomodulin and their receptors on vagal afferents represents another cornerstone in the metabolic reprogramming narrative. Postoperative elevations of these hormones are well documented to suppress appetite and improve insulin sensitivity. However, the exact mechanisms by which signals propagate along the vagus nerve to specific brainstem nuclei responsible for energy homeostasis remain incompletely understood. Blasi’s review highlights how NMDA receptor modulation could enhance or refine the fidelity of these afferent signals, thereby amplifying hormonal effects.

Additionally, the review contextualizes metabolic surgery within broader neuro-immune-metabolic frameworks. The gut-brain axis interfaces with systemic inflammation and immune signaling pathways, which are increasingly recognized as contributors to obesity-related insulin resistance. Altered vagal afferent signaling post-surgery may attenuate pro-inflammatory signaling cascades, further facilitating metabolic benefits. This holistic perspective underscores the necessity for integrative research approaches that consider neural, hormonal, and immune players simultaneously rather than in isolation.

From a translational standpoint, these insights carry enormous therapeutic potential. Current pharmacological efforts to emulate the benefits of metabolic surgery largely focus on gut hormone analogs and appetite suppressants. However, direct neuromodulation of vagal afferents through receptor-specific agents would offer unprecedented specificity and efficacy. Such therapies could potentially circumvent issues like drug resistance and adverse effects associated with systemic hormone administration, representing a precision medicine approach to obesity and diabetes.

Furthermore, the review stresses the importance of developing methodologies to monitor and quantify functional changes in the gut-brain axis in vivo. Advanced neuroimaging, optogenetics, and bioelectronic medicine technologies offer promising platforms to observe vagal afferent activity and synaptic remodeling dynamically. Bridging preclinical findings to human physiology will be crucial for validating NMDA subunit-targeted agents and optimizing therapeutic protocols.

While the complexity of the underlying biology poses challenges, Blasi’s synthesis injects renewed optimism and direction into the field. By framing metabolic surgery’s efficacy as the product of structured neural modulation, it invites a paradigm shift away from purely surgical or systemic pharmacological solutions. Instead, the focus pivots toward targeted molecular interventions at the intersection of neural networks and metabolic control circuits, heralding a new frontier in obesity treatment.

Importantly, this research trajectory aligns with broader efforts in neuromodulation therapies across multiple disciplines, including pain management, neuropsychiatry, and gastrointestinal motility disorders. The convergence of knowledge on vagus nerve physiology with metabolic pathology underscores the promise of cross-disciplinary innovation. Tailoring NMDA receptor modulation specifically to vagal afferents involved in energy homeostasis could pioneer a new class of bioelectronic or pharmacological devices with transformative impacts.

Moreover, the prospect of non-invasive or minimally invasive interventions inspired by these mechanisms carries striking implications for public health. Given the rising global prevalence of obesity and type 2 diabetes, scalable alternatives to metabolic surgery are urgently needed. Interventions capable of mimicking the surgery’s metabolic rewiring without incisions or hospital stays could dramatically increase accessibility, reduce costs, and alleviate surgical risks. Blasi’s call for focused research on these neural substrates thus has both scientific merit and societal urgency.

Looking forward, integrating multi-omics approaches including transcriptomics, proteomics, and metabolomics into the study of vagal afferent alterations could uncover novel biomarkers predictive of therapeutic responsiveness. This would facilitate patient stratification, guide dosing regimens, and improve long-term outcomes. Likewise, longitudinal clinical trials assessing neural function alongside metabolic endpoints will be essential to translate mechanistic findings into viable treatments.

In conclusion, Blasi’s review deftly amalgamates current knowledge surrounding metabolic surgery and its neurophysiological consequences, highlighting vagal afferent fibers and NMDA receptor subunits as keystones. This conceptual framework not only advances understanding of surgery’s efficacy but also unveils innovative directions for developing non-invasive therapies targeting the gut-brain axis. As science progresses, these insights may redefine obesity and diabetes management, shifting the paradigm towards precision neuro-metabolic modulation with immense transformative potential.

Subject of Research: Mechanisms underlying the effectiveness of metabolic surgery in obesity and type 2 diabetes, focusing on gut-brain axis functional changes and vagal afferent fibers.

Article Title: Mechanisms of metabolic surgery effectiveness in obesity and type 2 diabetes: a puzzle with some known pieces.

Article References:
Blasi, C. Mechanisms of metabolic surgery effectiveness in obesity and type 2 diabetes: a puzzle with some known pieces. Int J Obes (2025). https://doi.org/10.1038/s41366-025-01853-y

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s41366-025-01853-y

Keywords: Metabolic surgery, obesity, type 2 diabetes, gut-brain axis, vagal afferent fibers, NMDA receptors, neuroendocrine modulation, appetite regulation, glucose homeostasis, neuromodulation, non-invasive therapy