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Medial preoptic PNOC neurons constrain brown adipose tissue thermogenesis and energy expenditure

ABSTRACT: The preoptic area (POA) of the hypothalamus is a key neural hub for thermoregulation, yet its role in modulating energy expenditure during caloric excess remains poorly defined. Here, we characterize prepronociceptin (PNOC)-expressing neurons in the medial POA (PNOCmPOA) that inhibit brown adipose tissue (BAT) thermogenesis and systemic energy expenditure. Chemogenetic activation of PNOCmPOA neurons reduced BAT activity, core temperature, energy expenditure, and glucose tolerance through inhibitory projections to the dorsomedial hypothalamus (DMH). In contrast, silencing or ablation of PNOCmPOA neurons increased BAT thermogenesis. Furthermore, PNOCmPOA activation promoted non-REM sleep, coupling thermoregulatory and arousal states. These findings define a hypothalamic circuit that limits postprandial arousal, thermogenesis, and energy dissipation, contributing to the pathophysiology of obesity. Targeting the PNOCmPOA→DMH pathway may provide a new therapeutic strategy to enhance BAT function in metabolic disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE306829 | GEO | 2026/06/02

REPOSITORIES: GEO

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Medial preoptic PNOC neurons constrain brown adipose tissue thermogenesis and energy expenditure

Project description:The preoptic area (POA) of the hypothalamus is a key neural hub for thermoregulation, yet its role in modulating energy expenditure during caloric excess remains poorly defined. Here, we characterize prepronociceptin (PNOC)-expressing neurons in the medial POA (PNOCmPOA) that inhibit brown adipose tissue (BAT) thermogenesis and systemic energy expenditure. Chemogenetic activation of PNOCmPOA neurons reduced BAT activity, core temperature, energy expenditure, and glucose tolerance through inhibitory projections to the dorsomedial hypothalamus (DMH). In contrast, silencing or ablation of PNOCmPOA neurons increased BAT thermogenesis. Furthermore, PNOCmPOA activation promoted non-REM sleep, coupling thermoregulatory and arousal states. These findings define a hypothalamic circuit that limits postprandial arousal, thermogenesis, and energy dissipation, contributing to the pathophysiology of obesity. Targeting the PNOCmPOA→DMH pathway may provide a new therapeutic strategy to enhance BAT function in metabolic disease.

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The pesticide chlorpyrifos promotes obesity by inhibiting diet-induced thermogenesis in brown adipose tissue

Project description:Obesity results from a caloric imbalance between energy intake, absorption and expenditure. In both rodents and humans, diet-induced thermogenesis contributes to energy expenditure and involves the activation of brown adipose tissue (BAT). We hypothesized that environmental toxicants commonly used as food additives or pesticides might reduce BAT thermogenesis through suppression of uncoupling protein 1 (UCP1) and this may contribute to the development of obesity. Using a step-wise screening approach, we discovered that the organophosphate insecticide chlorpyrifos suppresses UCP1 and mitochondrial respiration in BAT at concentrations as low as 1 pM. In mice housed at thermoneutrality and fed a high-fat diet, chlorpyrifos impaired BAT mitochondrial function and diet-induced thermogenesis, promoting greater obesity, non-alcoholic fatty liver disease (NAFLD) and insulin resistance. This was associated with reductions in cAMP; activation of p38MAPK and AMPK; protein kinases critical for maintaining UCP1 and mitophagy, respectively in BAT. These data indicate that the commonly used pesticide chlorpyrifos, suppresses diet-induced thermogenesis and the activation of BAT, suggesting its use may contribute to the obesity epidemic.

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Project description:Brown adipose tissue (BAT) regulates whole-body energy balance through UCP1-dependent thermogenesis and secretion of metabolic factors. Our single-nucleus RNA sequencing of BAT from cold-exposed Ucp1 knockout mice reveals a distinct brown adipocyte subpopulation (U2). U2 adipocytes exhibit a secretory profile enriched in batokines like growth differentiation factor 15 (GDF15), suggesting a shift towards an endocrine role. Functional analyses reveal that GDF15-GFRAL signaling is required to sustain energy expenditure in adipose tissue (AT). Additionally, a conserved UCP1-GDF15 regulatory axis in human AT is observed.

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RNA sequencing of WT and ERRαγAd-/- brown adipose tissue treated with CL316,243

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Project description:Brown adipose tissue (BAT) is best known for thermogenesis. Whereas numerous studies in rodents found tight associations between the metabolic benefits of BAT and enhanced whole-body energy expenditure, emerging evidence in humans suggests that BAT is protective against Type 2 diabetes independent of body-weight. The underlying mechanism for this dissociation remained unclear. Here, we report that impaired mitochondrial flux of branched-chain amino acids (BCAA) in BAT, by deleting mitochondrial BCAA carrier (MBC, encoded by Slc25a44), was sufficient to cause systemic insulin resistance without affecting whole-body energy expenditure or body-weight. We found that brown adipocytes catabolized BCAAs in the mitochondria as essential nitrogen donors for the biosynthesis of glutamate, N-acetylated amino acids, and one of the products, glutathione. BAT-selective impairment in mitochondrial BCAA flux led to elevated oxidative stress and insulin resistance in the liver, accompanied by reduced levels of BCAA-nitrogen derived metabolites in the circulation. In turn, supplementation of glutathione restored insulin sensitivity of BAT-specific MBC knockout mice. Notably, a high-fat diet rapidly impaired BCAA catabolism and the synthesis of BCAA-nitrogen derived metabolites in the BAT, while cold-induced BAT activity is coupled with an active synthesis of these metabolites. Together, the present work uncovers a mechanism through which brown fat controls metabolic health independent of thermogenesis via BCAA-derived nitrogen carriers acting on the liver.

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