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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., (© 2024. The Author(s).)

Bile acids (BAs) improve metabolism and exert anti-obesity effects through the activation of the Takeda G protein-coupled receptor 5 (TGR5) in peripheral tissues. TGR5 is also found in the brain hypothalamus, but whether hypothalamic BA signaling is implicated in body weight control and obesity pathophysiology remains unknown. Here we show that hypothalamic BA content is reduced in diet-induced obese mice. Central administration of BAs or a specific TGR5 agonist in these animals decreases body weight and fat mass by activating the sympathetic nervous system, thereby promoting negative energy balance. Conversely, genetic downregulation of hypothalamic TGR5 expression in the mediobasal hypothalamus favors the development of obesity and worsens established obesity by blunting sympathetic activity. Lastly, hypothalamic TGR5 signaling is required for the anti-obesity action of dietary BA supplementation. Together, these findings identify hypothalamic TGR5 signaling as a key mediator of a top-down neural mechanism that counteracts diet-induced obesity., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Glucagon-like peptide 1 receptor (GLP-1R) agonists effectively improve glycemia and body weight in patients with type 2 diabetes and obesity but have limited weight-lowering efficacy and minimal insulin sensitizing action. In preclinical models, peripherally restricted cannabinoid receptor type 1 (CB1R) inhibitors, which are devoid of the neuropsychiatric adverse effects observed with brain-penetrant CB1R blockers, ameliorate obesity and its multiple metabolic complications. Using mouse models with genetic loss of CB1R or GLP-1R, we demonstrate that these two metabolic receptors modulate food intake and body weight via reciprocal functional interactions. In diet-induced obese mice, the coadministration of a peripheral CB1R inhibitor with long-acting GLP-1R agonists achieves greater reduction in body weight and fat mass than monotherapies by promoting negative energy balance. This cotreatment also results in larger improvements in systemic and hepatic insulin action, systemic dyslipidemia, and reduction of hepatic steatosis. Thus, peripheral CB1R blockade may allow safely potentiating the antiobesity and antidiabetic effects of currently available GLP-1R agonists., (© 2020 by the American Diabetes Association.)

The endocannabinoid system (ECS) plays a critical role in obesity development. The pharmacological blockade of cannabinoid receptor type 1 (CB(1)) has been shown to reduce body weight and to alleviate obesity-related metabolic disorders. An unsolved question is at which anatomical level CB(1) modulates energy balance and the mechanisms involved in its action. Here, we demonstrate that CB(1) receptors expressed in forebrain and sympathetic neurons play a key role in the pathophysiological development of diet-induced obesity. Conditional mutant mice lacking CB(1) expression in neurons known to control energy balance, but not in nonneuronal peripheral organs, displayed a lean phenotype and resistance to diet-induced obesity. This phenotype results from an increase in lipid oxidation and thermogenesis as a consequence of an enhanced sympathetic tone and a decrease in energy absorption. In conclusion, CB(1) signaling in the forebrain and sympathetic neurons is a key determinant of the ECS control of energy balance., (2010 Elsevier Inc. All rights reserved.)

One of the most interesting pharmacological targets proposed in the past ten years for fighting obesity and related metabolic disorders is the endocannabinoid system. The role of the endocannabinoid system is crucial in regulating the rewarding properties of food, in controlling energy balance by acting at the hypothalamic circuitries involved in food intake, and in peripheral metabolism by influencing adipocytes, hepatocytes, myocytes and pancreatic endocrine cells. Obesity seems to be a condition associated with a pathological overactivation of the endocannabinoid system; therefore, restoring a normal endocannabinoid tone by antagonizing the cannabinoid receptor type 1 (CB(1)) could help arrest both the development and the maintenance of obesity.

Metabolic flexibility allows rapid adaptation to dietary change, however, little is known about the CNS mechanisms regulating this process. Neurons in the hypothalamic ventromedial nucleus (VMN) participate in energy balance and are the target of the metabolically relevant hormone leptin. Cannabinoid type-1 (CB 1 ) receptors are expressed in VMN neurons, but the specific contribution of endocannabinoid signaling in this neuronal population to energy balance regulation is unknown. Here we demonstrate that VMN CB 1 receptors regulate metabolic flexibility and actions of leptin. In chow-fed mice, conditional deletion of CB 1 in VMN neurons (expressing the steroidogenic factor 1, SF1) decreases adiposity by increasing sympathetic activity and lipolysis, and facilitates metabolic effects of leptin. Conversely, under high-fat diet, lack of CB 1 in VMN neurons produces leptin resistance, blunts peripheral use of lipid substrates and increases adiposity. Thus, CB 1 receptors in VMN neurons provide a molecular switch adapting the organism to dietary change. [ABSTRACT FROM AUTHOR]

Summary: The endocannabinoid system (ECS) plays a critical role in obesity development. The pharmacological blockade of cannabinoid receptor type 1 (CB1) has been shown to reduce body weight and to alleviate obesity-related metabolic disorders. An unsolved question is at which anatomical level CB1 modulates energy balance and the mechanisms involved in its action. Here, we demonstrate that CB1 receptors expressed in forebrain and sympathetic neurons play a key role in the pathophysiological development of diet-induced obesity. Conditional mutant mice lacking CB1 expression in neurons known to control energy balance, but not in nonneuronal peripheral organs, displayed a lean phenotype and resistance to diet-induced obesity. This phenotype results from an increase in lipid oxidation and thermogenesis as a consequence of an enhanced sympathetic tone and a decrease in energy absorption. In conclusion, CB1 signaling in the forebrain and sympathetic neurons is a key determinant of the ECS control of energy balance. [Copyright &y& Elsevier]

Obesity has increased at a striking rate over the last 3 decades in the Western world. This negative trend dramatically affects physical health and, ultimately, cardiovascular risks. In fact, particularly at the visceral level, obesity is strongly associated with an increased risk for life-threatening conditions, such as type 2 diabetes mellitus, hypertension, dyslipidemia, and cardiovascular disease. Although nutritional changes and physical activity are commonly thought of as the core treatments for obesity, it is necessary to further support obese patients with a pharmacologic approach for 2 reasons: to reduce the metabolic risk profile, and to avoid the regaining of weight. Among the various pharmacologic targets explored in recent years, the endocannabinoid (EC) system now constitutes the most promising proposal so far. In this review, after focusing on the central and peripheral signaling pathways that preserve energy homeostasis, we review the role of the EC system in regulating food’s rewarding properties, controlling caloric intake by acting in hypothalamic pathways, and in modulating metabolic functions of several peripheral organs. In addition, we provide evidence that supports the recently proposed hypothesis that a close association exists between obesity and overactivation of the EC system. [Copyright &y& Elsevier]