Abstract:
To survive, animals must constantly balance the need to obtain food with the need to avoid danger. Feeding is essential, yet perceived danger shifts priority toward safety and transiently suppresses food intake, even when organisms are hungry. Hypothalamic pro-opiomelanocortin (POMC) neurons align metabolic outputs with energy demands and control feeding. However, the role of POMC neurons in determining the trade-off between feeding and threat responses remains unclear. Here, fasted mice are exposed to a fear-conditioning paradigm to examine how POMC neurons influence the choice between feeding and defensive behaviors. Behavioral analyses combined with chemogenetic, neuroanatomical, and molecular approaches show that activation of POMC neurons suppresses feeding during a learned threat and it is associated with corticotropin releasing hormone (CRH) neuron-dependent activation of the hypothalamic-pituitary-adrenal (HPA) axis. These effects require cannabinoid type 1 receptor (CB1R) signaling in POMC neurons, uncovering a POMC-CB1R pathway that tunes behavioral flexibility under a perceived threat. Collectively, the data identify POMC neurons as key integrators of metabolic and stress signals that bias decision making between feeding and threat-avoidance behaviors.

Abstract:
Hypothalamic pro-opiomelanocortin (POMC) neurons are classically viewed as mediators of satiety, acting in response to metabolic and hormonal cues and in opposition to Agouti-related protein (AgRP) neurons to maintain energy balance. This model, centered on the appetite-suppressant effects of the POMC-derived neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) through its activation of melanocortin-4 receptors (MC4R), has shaped our understanding of feeding and body weight regulation for decades. However, recent discoveries have challenged and expanded this traditional view, revealing that POMC neurons are not a uniform population dedicated solely to satiety control. Single-cell transcriptomic analyses have revealed striking molecular heterogeneity, reflected in distinct anatomical distributions, receptor expression profiles, electrophysiological properties, and projection patterns - all supporting the idea of functional specialization within this neuronal population. In this review, we propose a conceptual framework that integrates POMC neuronal heterogeneity with the regulation of appetite, metabolic physiology, and behavior beyond feeding. We highlight emerging evidence showing that discrete POMC neuronal subpopulations respond to specific combinations of interoceptive and environmental cues to orchestrate diverse adaptive responses. This perspective underscores the developmental plasticity and functional versatility of POMC neurons, offering new insights into the mechanisms of obesity and potentially paving the way for novel targeted therapeutic strategies.

Abstract:
OBJECTIVES: SF1 neurons of the ventromedial hypothalamus (VMH) play a pivotal role in regulating body weight and adiposity, particularly in response to a high-fat diet (HFD), as well as in the recovery from insulin-induced hypoglycemia. While the brain-specific CPT1C isoform is well known for its role in controlling food intake and energy homeostasis, its function within specific hypothalamic neuronal populations remains largely unexplored. Here, we explore the role of CPT1C in SF1 neurons. METHODS: Mice deficient in CPT1C within SF1 neurons were generated, and their response to a HFD was investigated. RESULTS: SF1-Cpt1c-KO mice fail to adjust their caloric intake during initial HFD exposure, which is associated with impaired activation of the melanocortin system. Furthermore, these mice exhibit disrupted metabolic gene expression in the liver, muscle, and adipose tissue, leading to increased adiposity independently of food intake. In contrast, their response to glucose or insulin challenges remains intact. After long-term HFD exposure, SF1-Cpt1c-KO mice are more prone to developing obesity and glucose intolerance than control littermates, with males exhibiting a more severe phenotype. Interestingly, CPT1C deficiency in SF1 neurons also results in elevated hypothalamic endocannabinoid (eCB) levels under both chow and HFD conditions. We propose that this sustained eCB elevation reduces VMH activation by fatty acids and impairs the SF1-POMC drive upon fat intake. CONCLUSION: Our findings establish CPT1C in SF1 neurons as essential for VMH-driven dietary fat sensing, satiety, and lipid metabolic adaptation.

Abstract:
In eukaryotic cells, the mammalian target of rapamycin complex 1 (sometimes referred to as the mechanistic target of rapamycin complex 1; mTORC1) orchestrates cellular metabolism in response to environmental energy availability. As a result, at the organismal level, mTORC1 signalling regulates the intake, storage and use of energy by acting as a hub for the actions of nutrients and hormones, such as leptin and insulin, in different cell types. It is therefore unsurprising that deregulated mTORC1 signalling is associated with obesity. Strategies that increase energy expenditure offer therapeutic promise for the treatment of obesity. Here we review current evidence illustrating the critical role of mTORC1 signalling in the regulation of energy expenditure and adaptive thermogenesis through its various effects in neuronal circuits, adipose tissue and skeletal muscle. Understanding how mTORC1 signalling in one organ and cell type affects responses in other organs and cell types could be key to developing better, safer treatments targeting this pathway in obesity.

Abstract:
The crucial role of the hypothalamus in the pathogenesis of obesity is widely recognized, while the precise molecular and cellular mechanisms involved are the focus of intense research. A disrupted endocannabinoid system, which critically modulates feeding and metabolic functions, through central and peripheral mechanisms, is a landmark indicator of obesity, as corroborated by investigations centered on the cannabinoid receptor CB1, considered to offer promise in terms of pharmacologically targeted treatment for obesity. In recent years, novel insights have been obtained, not only into relation to the mode of action of CB receptors, but also CB ligands, non-CB receptors, and metabolizing enzymes considered to be part of the endocannabinoid system (particularly the hypothalamus). The outcome has been a substantial expansion in knowledge of this complex signaling system and in drug development. Here we review recent literature, providing further evidence on the role of hypothalamic endocannabinoids in regulating energy balance and the implication for the pathophysiology of obesity. We discuss how these lipids are dynamically regulated in obesity onset, by diet and metabolic hormones in specific hypothalamic neurons, the impact of gender, and the role of endocannabinoid metabolizing enzymes as promising targets for tackling obesity and related diseases.

Abstract:
Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called 'hunger' hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB(2) receptors at the central nervous system (CNS) level. In a heterologous system we identified CB(2)-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB(2) receptor/G(i)-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB(2) receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB(2)-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.

Abstract:

Abstract:
The endocannabinoid (eCB) system regulates energy homeostasis and is linked to obesity development. However, the exact dynamic and regulation of eCBs in the hypothalamus during obesity progression remain incompletely described and understood. Our study examined the time course of responses in two hypothalamic eCBs, 2-arachidonoylglycerol (2-AG) and arachidonoylethanolamine (AEA), in male and female mice during diet-induced obesity and explored the association of eCB levels with changes in brown adipose tissue (BAT) thermogenesis and body weight. We fed mice a high-fat diet (HFD), which induced a transient increase (substantial at 7 days) in hypothalamic eCBs, followed by a progressive decrease to basal levels with a long-term HFD. This transient rise at early stages of obesity is considered a physiologic compensatory response to BAT thermogenesis, which is activated by diet surplus. The eCB dynamic was sexually dimorphic: hypothalamic eCBs levels were higher in female mice, who became obese at later time points than males. The hypothalamic eCBs time course positively correlated with thermogenesis activation, but negatively matched body weight, leptinemia, and circulating eCB levels. Increased expression of eCB-synthetizing enzymes accompanied the transient hypothalamic eCB elevation. Icv injection of eCB did not promote BAT thermogenesis; however, administration of thermogenic molecules, such as central leptin or a peripheral beta3-adrenoreceptor agonist, induced a significant increase in hypothalamic eCBs, suggesting a directional link from BAT thermogenesis to hypothalamic eCBs. This study contributes to the understanding of hypothalamic regulation of obesity.

Abstract:
OBJECTIVE: Carnitine palmitoyltransferase 1C (CPT1C) is implicated in central regulation of energy homeostasis. Our aim was to investigate whether CPT1C in the ventromedial nucleus of the hypothalamus (VMH) is involved in the activation of brown adipose tissue (BAT) thermogenesis in the early stages of diet-induced obesity. METHODS: CPT1C KO and wild type (WT) mice were exposed to short-term high-fat (HF) diet feeding or to intracerebroventricular leptin administration and BAT thermogenesis activation was evaluated. Body weight, adiposity, food intake, and leptinemia were also assayed. RESULTS: Under 7 days of HF diet, WT mice showed a maximum activation peak of BAT thermogenesis that counteracted obesity development, whereas this activation was impaired in CPT1C KO mice. KO animals evidenced higher body weight, adiposity, hyperleptinemia, ER stress, and disrupted hypothalamic leptin signaling. Leptin-induced BAT thermogenesis was abolished in KO mice. These results indicate an earlier onset leptin resistance in CPT1C KO mice. Since AMPK in the VMH is crucial in the regulation of BAT thermogenesis, we analyzed if CPT1C was a downstream factor of this pathway. Genetic inactivation of AMPK within the VMH was unable to induce BAT thermogenesis and body weight loss in KO mice, indicating that CPT1C is likely downstream AMPK in the central mechanism modulating thermogenesis within the VMH. Quite opposite, the expression of CPT1C in the VMH restored the phenotype. CONCLUSION: CPT1C is necessary for the activation of BAT thermogenesis driven by leptin, HF diet exposure, and AMPK inhibition within the VMH. This study underscores the importance of CPT1C in the activation of BAT thermogenesis to counteract diet-induced obesity.