Abstract:
Data accumulated over the last two decades have demonstrated that astrocytes play key roles in the regulation of synaptic transmission and plasticity. This is due, among other mechanisms, to their capability to detect and regulate synaptic transmission by expressing receptors and releasing gliotransmitters, respectively. Importantly, in juvenile rats, astrocytes are able to detect glutamate release at the level of individual synapses through mGluR5 and consequently up-regulate excitatory synaptic transmission efficacy through the release of purines. Whether this upregulation is still present in the adult brain is an open question. Using immunohistochemistry and RNAscope on fixed tissue, as well as electrophysiological recordings on acute hippocampal brain slices of adult male rats, we demonstrated that this regulatory pathway also prevails in adult rats. Most surprisingly, such facilitation of glutamate release that is readily observed when a small number of synapses are activated was completely abolished under conditions where a large number of inputs were stimulated. These findings thus suggest that astrocytes integrate the incoming afferent information and adapt their responses depending on the network activity.

Abstract:
Many diverse signals regulate feeding behavior. In Nature Metabolism, Xiao et al. describe the discovery of a new appetite-suppressant metabolite found in pythons, which is also conserved in humans. This research broadens our understanding of postprandial physiology and raises new questions related to metabolic pathology and therapy.

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:
Obesity-induced biological changes often persist after weight loss and are difficult to reverse, a phenomenon known as 'obesogenic memory'. This enduring effect is associated with metabolic inflammation, particularly in adipose tissue. In this study, we characterise a mouse model of obesogenic memory and evaluate the efficacy of the unimolecular conjugate GLP-1/Dexa, which selectively and safely delivers the anti-inflammatory drug dexamethasone to GLP-1 receptor (GLP-1R)-expressing cells. We document that this precision pharmacological approach outperforms treatment with GLP-1 or dexamethasone alone, significantly reducing body weight, food intake, adiposity and markers of adipose tissue inflammation in male mice with obesogenic memory. In addition, we identify the CCR2/CCL2 inflammatory pathway as an important mediator of glucose intolerance and adipose tissue inflammation associated with obesogenic memory. Our findings suggest that targeting inflammation via GLP-1R signalling may be a promising therapeutic strategy to alleviate obesogenic memory and improve the long-term clinical management of metabolic diseases.

Abstract:
OBJECTIVE: Steroidogenic factor-1 (SF1) neurons of the ventromedial hypothalamus play key roles in the regulation of food intake, body weight and glucose metabolism. The bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) is expressed in the hypothalamus, where it determines some of the actions of bile acids on food intake and body weight through still poorly defined neuronal mechanisms. Here, we examined the role of TGR5 in SF1 neurons in the regulation of energy balance and glucose metabolism. METHODS: We used a genetic approach combined with metabolic phenotyping and molecular analyses to establish the effect of TGR5 deletion in SF1 neurons on meal pattern, body weight, body composition, energy expenditure and use of energy substrates as well as on possible changes in glucose handling and insulin sensitivity. RESULTS: Our findings reveal that TGR5 in SF1 neurons does not play a major role in the regulation of food intake or body weight under standard chow, but it is involved in the adaptive feeding response to the acute exposure to cold or to a hypercaloric, high-fat diet, without changes in energy expenditure. Notably, TGR5 in SF1 neurons hinder glucose metabolism, since deletion of the receptor improves whole-body glucose uptake through heightened insulin signaling in the hypothalamus and in the brown adipose tissue. CONCLUSIONS: TGR5 in SF1 neurons favours satiety by differently modifying the meal pattern in response to specific metabolic cues. These studies also reveal a novel key function for TGR5 in SF1 neurons in the regulation of whole-body insulin sensitivity, providing new insight into the role played by neuronal TGR5 in the regulation of metabolism.

Abstract:
Glucagon-like peptide 1 (GLP-1) stimulates insulin secretion and holds significant pharmacological potential. Nevertheless, the regulation of energy homeostasis by centrally-produced GLP-1 remains partially understood. Preproglucagon cells, known to release GLP-1, are found in the olfactory bulb (OB). We show that activating GLP-1 receptors (GLP-1R) in the OB stimulates insulin secretion in response to oral glucose in lean and diet-induced obese male mice. This is associated with reduced noradrenaline content in the pancreas and blocked by an α(2)-adrenergic receptor agonist, implicating functional involvement of the sympathetic nervous system (SNS). Inhibiting GABA(A) receptors in the paraventricular nucleus of the hypothalamus (PVN), the control centre of the SNS, abolishes the enhancing effect on insulin secretion induced by OB GLP-1R. Therefore, OB GLP-1-dependent regulation of insulin secretion relies on a relay within the PVN. This study provides evidence that OB GLP-1 signalling engages a top-down neural mechanism to control insulin secretion via the SNS.

Abstract:
The hypothalamus contains a remarkable diversity of neurons that orchestrate behavioural and metabolic outputs in a highly plastic manner. Neuronal diversity is key to enabling hypothalamic functions and, according to the neuroscience dogma, it is predetermined during embryonic life. Here, by combining lineage tracing of hypothalamic pro-opiomelanocortin (Pomc) neurons with single-cell profiling approaches in adult male mice, we uncovered subpopulations of 'Ghost' neurons endowed with atypical molecular and functional identity. Compared to 'classical' Pomc neurons, Ghost neurons exhibit negligible Pomc expression and are 'invisible' to available neuroanatomical approaches and promoter-based reporter mice for studying Pomc biology. Ghost neuron numbers augment in diet-induced obese mice, independent of neurogenesis or cell death, but weight loss can reverse this shift. Our work challenges the notion of fixed, developmentally programmed neuronal identities in the mature hypothalamus and highlight the ability of specialised neurons to reversibly adapt their functional identity to adult-onset obesogenic stimuli.

Abstract:
OBJECTIVE: Intestinal gluconeogenesis (IGN), via the initiation of a gut-brain nervous circuit, accounts for the metabolic benefits linked to dietary proteins or fermentable fiber in rodents and has been positively correlated with the rapid amelioration of body weight after gastric bypass surgery in humans with obesity. In particular, the activation of IGN moderates the development of hepatic steatosis accompanying obesity. In this study, we investigated the specific effects of IGN on adipose tissue metabolism, independent of its induction by nutritional manipulation. METHODS: We used two transgenic mouse models of suppression or overexpression of G6pc1, the catalytic subunit of glucose-6 phosphatase, which is the key enzyme of endogenous glucose production specifically in the intestine. RESULTS: Under a hypercaloric diet, mice overexpressing IGN showed lower adiposity and higher thermogenic capacities than wild-type mice, featuring marked browning of white adipose tissue (WAT) and prevention of the whitening of brown adipose tissue (BAT). Sympathetic denervation restricted to BAT caused the loss of the antiobesity effects associated with IGN. Conversely, IGN-deficient mice exhibited an increase in adiposity under a standard diet, which was associated with decreased expression of markers of thermogenesis in both BAT and WAT. CONCLUSIONS: IGN is sufficient to activate the sympathetic nervous system and prevent the expansion and the metabolic alterations of BAT and WAT metabolism under a high-calorie diet, thereby preventing the development of obesity. These data increase knowledge of the mechanisms of weight reduction in gastric bypass surgery and pave the way for new approaches to prevent or cure obesity.

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.