Obesity currently affects more than one billion people worldwide and is classified by the World Health Organization as a chronic, multifactorial disease defined by the excessive accumulation of adipose tissue. Its consequences reach far beyond body weight, extending into type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease and several cancers. The global economic burden is projected to reach trillions of US dollars annually by 2035. Yet existing treatments remain imperfect. Lifestyle interventions suffer from poor long-term adherence and frequent weight regain; pharmacological options such as GLP-1 receptor agonists and orlistat carry side effects ranging from gastrointestinal distress to cardiovascular risks, along with substantial costs; and bariatric surgery, while effective, is invasive and accessible to only a small fraction of those who need it. This treatment gap has driven growing scientific interest in food-derived bioactives as safer, more accessible complements or alternatives.

Rhizomes—the underground stems of plants such as turmeric (Curcuma longa), ginger (Zingiber officinale) and kencur (Kaempferia galanga)—are dense repositories of polyphenols, flavonoids and essential oils. However, many of their most celebrated compounds, including curcumin, suffer from notoriously poor water solubility, rapid systemic clearance and low oral bioavailability, which sharply constrain their therapeutic efficacy in conventional preparations. Fermentation offers a bioprocessing solution. When microorganisms such as lactic acid bacteria or filamentous fungi colonize the starch- and fibre-rich rhizome matrix, their enzymes cleave glycosidic and ester linkages, deconjugate polyphenols and generate structurally novel metabolites that simply do not exist in the raw plant. In one striking example documented in the review, fermentation of wild turmeric (Curcuma aromatica) with the fungus Rhizopus oligosporus produced l-carnitine de novo—a compound essential for transporting fatty acids into mitochondria for fat burning—reaching concentrations of up to 242 micrograms per gram, despite being absent from the unfermented substrate.

The metabolic by-products of this microbial transformation fall under the heading of postbiotics, a term defined by the International Scientific Association for Probiotics and Prebiotics as preparations of inanimate microorganisms and their components that confer a health benefit. Unlike probiotics, postbiotics do not require viable microorganisms, offering advantages in shelf stability, safety and standardization. Key postbiotic constituents generated during rhizome fermentation include short-chain fatty acids, bacteriocins, exopolysaccharides, bioactive peptides and biotransformed polyphenolic metabolites. The review’s authors are careful to note a nomenclature issue: because most included studies did not confirm microbial inactivation before administering their preparations, the team distinguishes throughout between “fermented rhizome products” as whole matrices and postbiotics in the strict sense, reserving the latter term for the specific bioactive metabolites hypothesized to mediate the observed effects.

To build this mechanistic framework, the researchers conducted the review under PRISMA guidelines, prospectively registering the protocol in PROSPERO. They searched four major databases—PubMed, Scopus, Web of Science and Embase—covering all records through April 2026, and screened 1307 initial records down to ten studies that met rigorous inclusion criteria. These comprised eight in vivo animal studies and two in vitro cell-culture studies spanning five rhizome species, with turmeric the most frequently investigated. Fermentation organisms were dominated by lactic acid bacteria, particularly Lactobacillus plantarum and L. paracasei, alongside filamentous fungi including Aspergillus oryzae, Eurotium cristatum and Rhizopus oligosporus. Animal models ranged from high-fat-diet-induced obesity in C57BL/6 mice and Sprague-Dawley rats to genetic obesity in ob/ob mice and spontaneous obesity in OLETF rats. Risk of bias was assessed using SYRCLE’s tool for animal studies and the ToxRTool for in vitro work, with both cell-culture studies achieving the highest reliability category.

Perhaps the most compelling evidence came from the six studies that directly compared fermented against unfermented preparations. In every single head-to-head comparison, the fermented product outperformed its unfermented counterpart on at least one assessed outcome. Fermented Rhizoma Atractylodis Macrocephalae more effectively reduced adipose tissue weight and improved serum triglycerides than the raw rhizome. Fermented turmeric suppressed weight gain and modulated gut microbiota more powerfully than unfermented turmeric—even though fermentation had actually reduced its curcuminoid content, a paradox suggesting that benefits may flow from biotransformed compounds, enhanced bioavailability or fermentation-derived metabolites rather than the parent phytochemicals alone. Fermented Panax notoginseng uniquely suppressed food intake and produced stronger weight reduction than the raw preparation, while fermented Polygonatum polysaccharides showed superior inhibition of adipogenesis in vitro.

The gut microbiota emerged as a central mediator of these effects. Across four in vivo studies that profiled host gut bacteria, fermented rhizome treatment consistently improved the ratio of Bacteroidetes to Firmicutes—a microbial signature repeatedly disrupted in obesity—and restored alpha diversity toward levels seen in normal-diet controls. Particularly striking was the enrichment of Akkermansia muciniphila, a mucus-degrading bacterium strongly associated with improved metabolic health and reduced gut permeability, which appeared in three independent studies using taxonomically distinct rhizome species. Fermented turmeric treatment also elevated faecal acetic, propionic and butyric acids—short-chain fatty acids that act through G-protein-coupled receptors to regulate lipid oxidation, insulin secretion and energy expenditure. Butyrate in particular was linked to the activation of thermogenic pathways in brown adipose tissue through upregulation of the metabolic enzymes ACSM3 and HADH, providing a direct microbiota-to-calorie-burning communication axis.

At the molecular level, the review identified at least six mechanistic axes of action. Suppression of adipogenesis—the process by which precursor cells mature into fat-storing adipocytes—was the most broadly shared, with multiple studies reporting downregulation of the master transcription factors PPAR-γ and C/EBPα and their downstream lipogenic enzymes. Conversely, lipolysis was enhanced through upregulation of HSL and ATGL and activation of PKA signalling. AMP-activated protein kinase, or AMPK, served as a central convergence node; in the most mechanistically complete study, fermented turmeric activated the AMPK–SIRT1–PGC-1α signalling triad, restoring mitochondrial oxidative capacity and energy expenditure while simultaneously suppressing endoplasmic reticulum stress and Nox4-mediated oxidative damage. Additional axes included improved insulin signalling via the PI3K/Akt pathway, attenuation of inflammatory cytokines including TNF-α, IL-6 and IL-1β, restoration of intestinal barrier integrity with reduced circulating endotoxin, and modulation of hypothalamic appetite regulation.

The metabolic results across the animal studies were substantive. All eight in vivo studies reported reductions in body weight gain or adipose tissue mass, and lipid profiles improved consistently, with reductions in serum and hepatic triglycerides in seven studies and HDL-cholesterol increases in four. One dose-response study documented that fermented turmeric extract at 200 and 500 milligrams per kilogram reduced weight gain by 12 and 22 percent respectively, while raising HDL-cholesterol by 53 to 67 percent. Glucose metabolism improved in the four studies assessing it, with reductions in fasting glucose, insulin and HOMA-IR, and thermogenic markers such as UCP-1 and adiponectin rose across several investigations.

The authors temper their enthusiasm with appropriate scientific caution. Using the OHAT framework, they rated the certainty of evidence as low or very low across all mechanistic axes, reflecting an entirely preclinical evidence base with predominantly unclear-to-high risk of bias in areas such as randomization and blinding. Substantial heterogeneity—five rhizome species, seven fermentation organisms, three product forms and multiple obesity models—prevented even a restricted quantitative meta-analysis. No human clinical data exist for these preparations. Nevertheless, the mechanistic coherence and cross-species consistency of the findings provide a preliminary foundation for the development of rhizome-based functional foods. The research team calls for randomized human intervention trials with standardized preparations, germ-free animal models to formally establish causal microbiota mechanisms, and bioactivity-guided fractionation to attribute specific effects to defined postbiotic compounds. If those trials succeed, the humble fermenting vat—humanity’s oldest food technology—may yet yield a new generation of evidence-based dietary tools against obesity.

The central focus of this study was to interrogate whether cold-sensitive engrams—the physical neural substrates of memory formed under cold exposure—play an active, causal role in systemic metabolic regulation. Using transgenic mouse models, the scientists selectively labelled cold-responsive neuronal populations in the DG during cold exposure (termed CL1). Subsequent optogenetic reactivation of these labelled cells in a neutral ambient temperature environment elicited significant increases in oxygen consumption, a robust indicator of metabolic activity. This artificial stimulation thereby mimicked the physiological metabolic boost normally prompted by cold exposure itself.

Detailed temporal analysis revealed that metabolic rate surges occurred specifically during laser-on intervals when cold-sensitive engrams were activated, returning promptly to baseline levels once stimulation ceased. Intriguingly, this effect attenuated upon a third consecutive stimulation session, implying potential habituation within the downstream pathways or limitations inherent to neuronal optogenetic activation. The reproducibility of these outcomes was confirmed across different transgenic systems, including those utilizing the FOS-tTa labelling framework, demonstrating the robustness of cold-engram manipulation in controlling metabolism.

To rigorously validate these observations, the researchers conducted control experiments targeting DG engrams labeled in the absence of cold exposure—termed “no-cold” engrams. Optogenetic activation of these non-cold contextual engrams yielded no significant enhancement in whole-body metabolic rate. In several instances, stimulation of no-cold engrams even elicited slight decreases in oxygen consumption, reinforcing the specificity of cold-sensitive engram activation in driving metabolic changes. Comparative analyses underscored that the pronounced oxygen consumption rise was unique to cold-exposed animals during light-induced reactivation.

Extending beyond the hippocampus, the team probed the downstream brain regions implicated in thermoregulatory control. By combining channelrhodopsin-assisted DG stimulation with brain-wide labelling of engram cells using eYFP fluorescence, they mapped coactivation patterns in hypothalamic nuclei. Significant increases in co-labelled neurons occurred in the lateral hypothalamic area (LHA) and medial preoptic (MPO) hypothalamic regions, but not in the lateral preoptic area (LPO). This selective regional involvement suggests that the DG’s cold-sensitive engrams interface functionally with specific hypothalamic circuits orchestrating systemic metabolic output.

Moreover, a compelling positive correlation emerged between oxygen consumption and the extent of artificial engram activity within the LHA, highlighting this region’s pivotal role in mediating learned thermoregulatory responses. These data intimate a circuit architecture whereby cold memory engrams in the hippocampus transmit signals to hypothalamic hubs, ultimately governing metabolic rate adjustments to optimize energy expenditure following environmental challenges.

To translate these neural manipulations into peripheral metabolic outcomes, the investigators evaluated thermogenesis gene expression profiles within BAT—an organ central to heat generation and energy homeostasis. Reactivation of cold-sensitive hippocampal engrams markedly elevated expression of Ucp1 and Cpt1a, key genes implicated in mitochondrial uncoupling and fatty acid oxidation, respectively. These molecular changes mirror physiological cold adaptation where BAT activity is upregulated to maintain core temperature. Notably, no alterations were observed in other thermogenic markers such as Hsl, Atgl, or Ppargc1a, indicating a targeted transcriptional response.

Together, the findings establish a paradigm wherein cold exposure leaves persistent neuronal “imprints” in the hippocampus that can be recalled to activate systemic thermogenic mechanisms even in the absence of external cold stimuli. This neural ‘memory’ of cold effectively modulates hypothalamic circuits and peripheral metabolic tissues to orchestrate complex physiological responses critical for survival. The precise manipulation of these engrams reveals the power of memory traces not only in cognition but in whole-body energy balance.

The attenuation of metabolic responses upon repeated engram stimulations observed in the study also prompts intriguing questions about neural plasticity and adaptation in this pathway. It may reflect synaptic fatigue, recruitment of inhibitory feedback loops, or homeostatic mechanisms limiting overstimulation of thermogenic systems to prevent adverse effects. Future research will be necessary to dissect these mechanisms and determine how persistent or flexible the memory-driven thermoregulatory system is.

This work elegantly combines cutting-edge optogenetics, genetic labelling strategies, and metabolic phenotyping to bridge the gap between experiential memory and physiological regulation. By identifying the hippocampus, a region typically associated with declarative memory, as a key player in energy balance, the research challenges classical circuit models of thermoregulation and opens new landscapes for exploring memory-dependent metabolic control.

Applications of this knowledge could extend to novel interventions in metabolic diseases such as obesity or hypothermia, whereby targeted activation or repression of memory engrams might recalibrate energy expenditure. Moreover, understanding the neurobiology of environmental memory could have broad implications for adaptation to climate variability or seasonal changes.

The integration of behavioral neuroscience with whole-body physiology marks a transformative approach, illustrating how experiential neural circuits transcend cognitive roles to govern vital homeostatic functions. As such, these insights are poised to stimulate cross-disciplinary research efforts and inspire new conceptual frameworks in neuro-metabolism.

Ultimately, the demonstration that “cold memories” exert causal control over metabolism underscores the elegance of adaptive biological systems: encoding not just the past, but banking on experience to anticipate physiological needs. This innovative research not only deciphers the neural codes of environmental adaptation but also paves the way for harnessing memory circuits to modulate somatic health.

Subject of Research: Memory engrams and their role in regulating whole-body metabolism and thermogenesis.

Article Title: Cold memories control whole-body thermoregulatory responses.

Article References:
Muñoz Zamora, A., Douglas, A., Conway, P.B. et al. Cold memories control whole-body thermoregulatory responses. Nature (2025). https://doi.org/10.1038/s41586-025-08902-6

Image Credits: AI Generated