bims-meneob 2026-03-01 papers

bims-meneob

Biomed News

on Metabolism Neuroscience Obesity

Issue of 2026–03–01
eight papers selected by
Mohammed K Hankir, Trinity College Dublin

Obesogenic effects of warm temperature involve feeding adaptation by preoptic area leptin receptor neurons.
Targeting Gβγ subunits in hypothalamic AgRP neurons to treat obesity.
GPR75 in glutamatergic neurons regulates body weight.
A Preoptic Neurocircuit That Modulates Metabolic Flexibility.
Central Irisin Administration Attenuates Hypothalamic TLR4/MyD88-Mediated Neuroinflammatory Signaling in Diet-Induced Obese Mice.
Brain-derived ketone bodies can replace glucose to power neural function.
Retatrutide Shows Multiple Metabolic Benefits in Diet-Induced Obese MASH Mouse and Hamster Models.
Prefrontal-medullary circuitry is necessary for sex-specific responses to metabolic stress in rats.

Commun Biol. 2026 Feb 23.

Obesogenic effects of warm temperature involve feeding adaptation by preoptic area leptin receptor neurons.

Laura Kaiser, Nathan Lee, Katelynn Zaunbrecher, Clint Kinney, Jaclyn Williams, Michael Smith, Robert C Noland, Sangho Yu, Christopher D Morrison, Hans-Rudolf Berthoud, Heike Münzberg.

The preoptic area (POA) is a well-established regulator of body temperature, but its role in feeding behavior remains underexplored. Our study identifies leptin receptor (Lepr)-expressing neurons in the POA (POALepr) as critical component to suppress food intake (FI) and increase satiety in response to warm ambient temperatures. Utilizing chemogenetic activation in mice of both sexes, we demonstrate that selective activation of POALepr neurons mimics the effects of warm temperatures, leading to a significant reduction in FI. POALepr neurons project to the melanocortin pathway, where activation of melanocortin-4 receptors (MC4R) also suppresses FI in a temperature-dependent manner. Our findings suggest that POALepr neurons integrate thermal and metabolic cues, demonstrating that ambient temperature is an integral part of body weight homeostasis by modulating meal size and satiety via POALepr neurons. These results offer new insights into the neurochemical and functional properties of POA functions, expanding the traditional view that the POA is exclusively involved in thermoregulation and underscoring its broader role in energy balance.

DOI: https://doi.org/10.1038/s42003-026-09723-7
Metabolism. 2026 Feb 19. pii: S0026-0495(26)00079-X. [Epub ahead of print] 156569

Targeting Gβγ subunits in hypothalamic AgRP neurons to treat obesity.

Ye Xuan, Xiaoyue Xiong, Xinyu Wang, Yunqi Wang, Yun Shen, Hong Zhang, Rong Zhang, Liwei Chen, Peng Zhang, Yi Zhang, Cheng Hu.

  G protein-coupled receptors (GPCRs) in the central nervous system, particularly in the hypothalamus, are promising therapeutic targets for the treatment of obesity and related metabolic disorders. However, the development of anti-obesity drugs targeting GPCRs in hypothalamus has been significantly constrained by their propensity to induce a range of adverse effects. An alternative strategy is to directly target the G protein subunits downstream of GPCRs, potentially biasing GPCR signaling away from harmful pathways while preserving those essential for normal cellular functions. The G protein βγ (Gβγ) subunits have emerged as a potential therapeutic target, but its role in obesity is largely unknown. In this study, we found that gallein, a Gβγ inhibitor, can ameliorate diet-induced obesity (DIO) and related metabolic dysfunction by suppressing appetite. Given the critical role of hypothalamic orexigenic Agouti-related peptide (AgRP)-expressing neurons in maintaining whole-body energy balance, we further demonstrated that gallein suppressed appetite by inhibiting AgRP neuronal activity. More importantly, specific inhibition of Gβγ subunits in AgRP neurons can inhibit the activation of AgRP neurons, thereby reducing food intake and ameliorating DIO and related metabolic dysfunction. Conversely, overexpression of Gβγ in AgRP neurons promoted hyperphagia and obesity. Mechanistically, we discovered that Gβγ subunits increase AMPK activity to promote mitochondrial fatty acid oxidation and ATP production, ultimately increasing the activity of AgRP neurons and related peptide expression. In conclusion, our study demonstrates that Gβγ subunits regulate feeding and metabolism through multiple bioenergetic processes in AgRP neurons. Gallein, the small-molecule inhibitor of Gβγ subunits emerges as a promising therapeutic candidate for obesity and its associated comorbidities.

Keywords:  AgRP neurons; Food intake; Gallein; Gβγ; Hypothalamus; Obesity

DOI:  https://doi.org/10.1016/j.metabol.2026.156569
Cell Rep. 2026 Feb 20. pii: S2211-1247(26)00089-6. [Epub ahead of print]45(3): 117011

GPR75 in glutamatergic neurons regulates body weight.

Steven C Wyler, Surbhi Gahlot, Lara Bideyan, Kyle Brown, Jennifer K Schiavo, Marco Galvan, Shreya Thomas, Arely Tinajero, Adan Khan, Warda Merchant, Laurent Gautron, Young-Jai You, Jason W Mastaitis, Judith Y Altarejos, Teppei Fujikawa, Joel K Elmquist.

  The G-protein-coupled receptor 75 (GPR75) emerged as a promising therapeutic target for treating diet-induced obesity (DIO). Loss-of-function mutations of GPR75 in humans are associated with reduced body mass index (BMI). Also, Gpr75-deficient mice are protected from DIO. Here, we generated genetically modified mice that enable us to selectively delete or reactivate Gpr75 in a Cre-dependent manner. Loss of Gpr75 in vGlut2+ glutamatergic neurons (Gpr75vGlut2-KO) results in protection against high-fat diet (HFD)-induced weight gain, whereas loss of Gpr75 in GABAergic neurons shows no protection against DIO. Furthermore, male Gpr75vGlut2-KO mice have reduced food intake on HFD without a change in energy expenditure. Reactivation of Gpr75 only in vGlut2-expressing cells in a Gpr75 null mouse (Gpr75TB) completely rescues the HFD-induced weight gain, whereas reactivation in GABAergic cells has no effect on body weight or adiposity. These complementary results demonstrate the importance of glutamatergic neurons in GPR75's regulation of food intake and protection from obesity.

Keywords:  CP: metabolism; CP: neuroscience; GABAergic; Gpr75; body weight; food intake; glutamatergic neurons; high fat diet; metabolic; obesity

DOI:  https://doi.org/10.1016/j.celrep.2026.117011
bioRxiv. 2026 Feb 14. pii: 2026.01.15.699760. [Epub ahead of print]

A Preoptic Neurocircuit That Modulates Metabolic Flexibility.

Julian M Roessler, Matthew Alkire, Nathan Nigrin, Haorui Wang, Christopher M Reid, Marissa D Cortopassi, Millenia Waite, Brooke Linnehan, Eric C Griffith, Mollie Madigan, Tenzin Kunchok, Alexander S Banks, Fabian Schulte, Bukyung Kim, Bo-Yeon Kim, Jason K Kim, Siniša Hrvatin.

Precise, dynamic control of metabolic fuel usage in response to environmental challenges such as altered food availability or temperature change is essential for animal survival. In mammals, metabolic flexibility-the capacity to shift cellular metabolism between carbohydrate and fatty acid oxidation-is understood to be largely regulated by circulating hormones such as insulin and glucagon. However, the role of the central nervous system in coordinating fuel selection and tissue metabolic tuning remains underexplored. Here, we investigated the mechanisms that mediate metabolic reprogramming following the acute activation of torpor-associated glutamatergic Adcyap1+ torpor-regulating neurons in the anteroventral preoptic area (avPOA Vglut2/PACAP ). The activation of these neurons rapidly shifts whole-body fuel use from glucose to fatty acids, irrespective of fuel/food availability. This shift is associated with reduced glucose utilization stemming from the transient induction of selective insulin resistance in skeletal muscle. We find that this reduction in skeletal muscle glucose metabolism does not require direct muscle innervation but is rather mediated in part via corticosterone. In contrast to their activation, avPOA Vglut2/PACAP neuronal silencing results in improved glucose tolerance, demonstrating powerful bidirectional control of tissue-specific glucose metabolism, whole-body glucose levels, and fuel usage. Together, our findings uncover a novel POA -skeletal muscle pathway that dynamically controls glucose utilization and metabolic flexibility.

DOI: https://doi.org/10.64898/2026.01.15.699760
Mol Neurobiol. 2026 Feb 27. pii: 473. [Epub ahead of print]63(1):

Central Irisin Administration Attenuates Hypothalamic TLR4/MyD88-Mediated Neuroinflammatory Signaling in Diet-Induced Obese Mice.

Kelly Cristina Pereira Bem, Tassiana Cristina Talpo, Guilherme Augusto da Silva Nogueira, Ariane Maria Zanesco, Davi Sidarta-Oliveira, Joel Alves da Silva Junior, Antonio Carlos Boschero, Licio Augusto Velloso, Helena Cristina de Lima Barbosa.

  Hypothalamic inflammation represents a central mechanism linking obesity to metabolic dysfunction. This process involves glial activation and persistent innate immune signaling, with Toll-like receptor 4 (TLR4) emerging as a critical interface between inflammatory pathways and impaired central insulin signaling. Irisin, a myokine released in response to physical exercise, has been shown to exert metabolic and anti-inflammatory effects in peripheral tissues, as well as neuroprotective actions in the brain. However, whether irisin directly modulates obesity-associated hypothalamic inflammation, particularly through TLR4-dependent pathways, remains unknown. Here, we investigated the effects of short-term intracerebroventricular delivery of recombinant irisin on hypothalamic inflammatory signaling in diet-induced obese mice. Central irisin administration reduced glial reactivity, downregulated components of the TLR4/MyD88 pathway, and increased the expression of anti-inflammatory cytokines in the hypothalamus. In addition, irisin restored insulin-stimulated AKT phosphorylation and selectively reduced inguinal white adipose tissue mass without affecting overall body weight. Together, these findings indicate that central irisin administration attenuates obesity-related hypothalamic inflammation and modulates central insulin signaling, supporting a role for irisin as a regulator of neuroinflammation-linked metabolic dysfunction.

Keywords:  Diet-induced obesity; Hypothalamic inflammation; Insulin resistance; Irisin; Toll-like receptor 4; Gliosis

DOI:  https://doi.org/10.1007/s12035-026-05729-8
bioRxiv. 2026 Feb 20. pii: 2026.02.19.706813. [Epub ahead of print]

Brain-derived ketone bodies can replace glucose to power neural function.

Hafsa Yaseen, Karissa Cisneros, Rebecca Wright, Nikolaus Bueschke, Joseph M Santin.

The brain is sensitive to disruptions in glucose metabolism, requiring constant delivery to support neural activity. Here, we discovered a vertebrate with the surprising capacity to abandon glucose metabolism and replace it with ketone bodies produced entirely within the brain. In frogs-animals with seemingly typical glucose demands-hibernation shifts brain bioenergetics to allow ketone bodies made within the brain to sustain neural activity without ATP from glucose metabolism. This involves, in part, the upregulation of fatty acid catabolism, ketone body synthesis, and transport from astrocytes to neurons to maintain synaptic transmission. Brain-derived ketone bodies also prevent decrements in activity that otherwise occur during hypoxia. These results provide insight into how frogs restart brain circuits following months of underwater hibernation when facing severe hypoxia and hypoglycemia that otherwise impair neural performance. Overall, these results reveal a capacity for the vertebrate brain to temporarily abandon glucose while maintaining costly functions using locally sourced ketone bodies independent from body energy stores.

DOI: https://doi.org/10.64898/2026.02.19.706813
Obesity (Silver Spring). 2026 Feb 25.

Retatrutide Shows Multiple Metabolic Benefits in Diet-Induced Obese MASH Mouse and Hamster Models.

François Briand, Camille Le Cudennec, Estelle Grasset, Natalia Breyner, Claire Bigot, Pierre Dillard, Thierry Sulpice.

   OBJECTIVE/METHODS: Our aim was to evaluate the efficacy of the triple glucagon, GIP, and GLP-1 receptor agonist retatrutide in diet-induced obese MASH mouse and hamster models, two preclinical models that we routinely use for assessing new therapies targeting obesity.
RESULTS: In mice, retatrutide strongly reduced body weight by 31% (p < 0.0001 vs. vehicle), both fat and lean mass, and food and water intake during the first days of treatment, while energy expenditure was not altered significantly. Retatrutide markedly reduced the HOMA-IR index of insulin resistance, hepatic steatosis score, fatty acids, triglycerides, and total cholesterol content. In hamsters, retatrutide altered food preference with increased chow diet intake and decreased high fat/cholesterol diet and 10% fructose water intake. The significant weight loss was associated with a reduction in fat and lean mass, but the lean mass was not different after 5 weeks of treatment with no change in mineral bone density. Retatrutide significantly reduced HOMA-IR, plasma triglycerides, and LDL-cholesterol levels. Although retatrutide did not reduce histopathological scoring, there was a 50% reduction in hepatic triglyceride content (p < 0.01).
CONCLUSIONS: Retatrutide demonstrates multiple metabolic benefits in both mouse and hamster models. Our preclinical setting will help to assess the efficacy of novel therapies targeting obesity and MASH.

Keywords:  MASH; hamster; mouse; obesity; retatrutide

DOI:  https://doi.org/10.1002/oby.70155
bioRxiv. 2026 Feb 12. pii: 2026.02.10.705203. [Epub ahead of print]

Prefrontal-medullary circuitry is necessary for sex-specific responses to metabolic stress in rats.

Carley Dearing, Ema Lukinic, Carlie McCartney, Brent Myers.

Chronic stress increases risk for metabolic disorders, including diabetes mellitus. Additionally, projections from the infralimbic cortex (IL) to the rostral ventrolateral medulla (RVLM) regulate endocrine stress responses. However, the neurobiological basis for chronic stress effects on glucose homeostasis has not been identified. The current study tests the hypothesis that the IL-RVLM circuit is necessary to prevent glucose intolerance. Accordingly, male and female rats with Cre-dependent expression of tetanus toxin light chain (TeLC) to inhibit neurotransmitter release from RVLM-projecting IL neurons were subject to chronic variable stress (CVS) or remained as No CVS controls. Animals were then acutely challenged with a fasted intraperitoneal glucose tolerance test (GTT). Endocrine metabolic function was evaluated during GTT via time courses of glucose, insulin, glucagon, and corticosterone. In No CVS females expressing TeLC, inhibition of IL-RVLM circuit signaling impaired glucose tolerance characterized by elevated glucose and decreased insulin sensitivity. Following chronic stress, females had impaired glucoregulation characterized by decreased glucose clearance and elevated corticosterone. When combined with TeLC, chronically-stressed females showed shifts in the ratio of insulin to glucagon compared to CVS GFP females, suggesting circuit function impacts the pancreatic mechanisms mediating glucose homeostasis during chronic stress. In No CVS males, TeLC increased glucagon only. However, CVS TeLC males had impaired glucose tolerance, reduced insulin sensitivity, and decreased corticosterone. These data indicate that the IL-RVLM circuit mediates glucoregulation in a manner dependent on both sex and stress history. Collectively, the IL-RVLM circuit is necessary for the sex-specific maintenance of glucose homeostasis following chronic stress.

DOI: https://doi.org/10.64898/2026.02.10.705203