Cristina Cervino

The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis

The cannabinoid receptor type 1 (CB1) and its endogenous ligands, the endocannabinoids, are involved in the regulation of food intake. Here we show that the lack of CB1 in mice with a disrupted CB1 gene causes hypophagia and leanness. As compared with WT (CB1+/+) littermates, mice lacking CB1 (CB1-/-) exhibited reduced spontaneous caloric intake and, as a consequence of reduced total fat mass, decreased body weight. In young CB1-/- mice, the lean phenotype is predominantly caused by decreased caloric intake, whereas in adult CB1-/- mice, metabolic factors appear to contribute to the lean phenotype. No significant differences between genotypes were detected regarding locomotor activity, body temperature, or energy expenditure. Hypothalamic CB1 mRNA was found to be coexpressed with neuropeptides known to modulate food intake, such as corticotropin-releasing hormone (CRH), cocaine-amphetamine-regulated transcript (CART), melanin-concentrating hormone (MCH), and preproorexin, indicating a possible role for endocannabinoid receptors within central networks governing appetite. CB1-/- mice showed significantly increased CRH mRNA levels in the paraventricular nucleus and reduced CART mRNA levels in the dorsomedial and lateral hypothalamic areas. CB1 was also detected in epidydimal mouse adipocytes, and CB1-specific activation enhanced lipogenesis in primary adipocyte cultures. Our results indicate that the cannabinoid system is an essential endogenous regulator of energy homeostasis via central orexigenic as well as peripheral lipogenic mechanisms and might therefore represent a promising target to treat diseases characterized by impaired energy balance.

CB(1) signaling in forebrain and sympathetic neurons is a key determinant of endocannabinoid actions on energy balance.

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.

Cannabinoid Type 1 Receptor Blockade Promotes Mitochondrial Biogenesis Through Endothelial Nitric Oxide Synthase Expression in White Adipocytes

OBJECTIVE—Cannabinoid type 1 (CB1) receptor blockade decreases body weight and adiposity in obese subjects; however, the underlying mechanism is not yet fully understood. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) induces mitochondrial biogenesis and function in adipocytes. This study was undertaken to test whether CB1 receptor blockade increases the espression of eNOS and mitochondrial biogenesis in white adipocytes. RESEARCH DESIGN AND METHODS—We examined the effects on eNOS and mitochondrial biogenesis of selective pharmacological blockade of CB1 receptors by SR141716 (rimonabant) in mouse primary white adipocytes. We also examined eNOS expression and mitochondrial biogenesis in white adipose tissue (WAT) and isolated mature white adipocytes of CB1 receptor–deficient (CB1−/−) and chronically SR141716-treated mice on either a standard or high-fat diet. RESULTS—SR141716 treatment increased eNOS expression in cultured white adipocytes. Moreover, SR141716 increased mitochondrial DNA amount, mRNA levels of genes involved in mitochondrial biogenesis, and mitochondrial mass and function through eNOS induction, as demonstrated by reversal of SR141716 effects by small interfering RNA–mediated decrease in eNOS. While high-fat diet–fed wild-type mice showed reduced eNOS expression and mitochondrial biogenesis in WAT and isolated mature white adipocytes, genetic CB1 receptor deletion or chronic treatment with SR141716 restored these parameters to the levels observed in wild-type mice on the standard diet, an effect linked to the prevention of adiposity and body weight increase. CONCLUSIONS—CB1 receptor blockade increases mitochondrial biogenesis in white adipocytes by inducing the expression of eNOS. This is linked to the prevention of high-fat diet–induced fat accumulation, without concomitant changes in food intake.

The Endocannabinoid System and Energy Metabolism

Many different regulatory actions have been attributed to endocannabinoids, and their involvement in several pathophysiological conditions is under intense scrutiny. Cannabinoid receptors [cannabinoid receptor type 1 (CB1) and CB2] participate in the physiological modulation of many central and peripheral functions. The ability of the endocannabinoid system to control appetite, food intake and energy balance has recently received considerable attention, particularly in the light of the different modes of action underlying these functions. The endocannabinoid system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, CB1 receptors and endocannabinoids are integrated components of the networks controlling appetite and food intake. Interestingly, the endocannabinoid system was recently shown to control several metabolic functions by acting on peripheral tissues such as adipocytes, hepatocytes, the gastrointestinal tract, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the endocannabinoid system occurs, and therefore drugs interfering with this overactivation by blocking CB1 receptors are considered as potentially valuable candidates for the treatment of obesity and related cardiometabolic risk factors.

Cannabinoid Type 1 Receptor: Another Arrow in the Adipocytes’ Bow

The endocannabinoid system has recently emerged as an important modulator of several functions of adipose tissue, including cell proliferation, differentiation and secretion. Here, we will review the effects of cannabinoid type 1 (CB1) receptor activation/blockade in adipocytes by summarising the data in the literature since the discovery of the presence of this receptor in adipose tissue. We will also discuss our original data obtained in mouse 3T3‐L1 adipocyte cells using WIN55 212, a CB1/CB2 receptor agonist and SR141716 (rimonabant), a specific CB1 receptor antagonist, respectively, in different experimental settings.

How many sites of action for endocannabinoids to control energy metabolism

The promising results obtained by clinical trials using Rimonabant to tackle visceral obesity and related disorders recently promoted a remarkable impulse to carry out detailed investigations into the mechanisms of action of endocannabinoids in regulating food intake and energy metabolism. The endocannabinoid system has been known for many years to play an important role in the modulation of the neuronal pathways mediating the rewarding properties of food. However, in the last few years, with the advanced understanding of the crucial role of the hypothalamic neuronal network in the regulation of appetite, several studies have also directed attention to the orexigenic role of the endocannabinoid system, substantiating the well known appetite stimulating properties of derivatives of Cannabis sativa. Furthermore, the last 2 years have seen a number of relevant publications emphasizing the role of endocannabinoids as significant players in various peripheral metabolic processes. To date, the roles of the endocannabinoid system in influencing energy metabolism have proved to be more complex than was formerly believed. However, the diverse ability to modulate both central and peripheral processes highlights the pivotal involvement of the endocannabinoid system in the control of metabolic processes. This review describes the roles of endocannabinoids and the cannabinoid type 1 receptor (CB1) in the control of energy balance.

Cannabinoid Receptor Antagonists and the Metabolic Syndrome: Novel Promising Therapeutical Approaches

Recent findings in animals and in humans have shown that cannabinoid type 1 receptor antagonists are suitable to become the most promising validated class of drugs to tackle obesity and related disorders. This mini-review will provide a concise and updated revision of the state of art on this topic.

Feeding disorders and obesity.

The ability of the endocannabinoid (EC) system to control appetite, food intake and energy balance has recently received great attention, particularly in the light of the different modes of action underlying these functions. The EC system modulates rewarding properties of food by acting at specific mesolimbic areas in the brain. In the hypothalamus, cannabinoid type 1 receptors (CB1) and ECs are integrated components of the networks controlling appetite and food intake. Interestingly, the EC system has recently been shown to control several metabolic functions by acting on peripheral tissues, such as adipocytes, hepatocytes, the skeletal muscles and the endocrine pancreas. The relevance of the system is further strengthened by the notion that visceral obesity seems to be a condition in which an overactivation of the EC system occurs; therefore, drugs interfering with this overactivation by blocking CB1 receptors are considered valuable candidates for the treatment of obesity and related cardiometabolic risk factors.

Il sistema endocannabinoide e l’obesità: prospettive terapeutiche

RiassuntoLa crescita esponenziale dell’obesità se da un lato ha prodotto un vistoso allarme socio-sanitario, dall’altro, ha dato un vigoroso impulso allo studio dei meccanismi patogenetici che portano al suo sviluppo e mantenimento. Dal 1994, anno della scoperta di leptina, una straordinaria serie di acquisizioni ha cominciato a far luce sui meccanismi che controllano l’introito alimentare e l’omeostasi energetica. Si è così evidenziato come l’ipotalamo elabori i segnali riguardo lo stato nutritivo come percepito dalla periferia e come da quest’area cerebrale vengano a loro volta dirottati agli organi periferici impulsi volti ad orientare il comportamento alimentare. Tra gli attori di tale comunicazione centro-periferia il sistema cannabinoide endogeno si è posto recentemente alla ribalta per la capacità inusuale di agire ad entrambi i livelli, sia centralmente che in periferia. In questo articolo descriveremo il ruolo del sistema endocannabinoide nel controllo del bilancio energetico, valutando le sue implicazioni nella regolazione delle proprietà gratificanti del cibo, nella modulazione dei circuiti ipotalamici coinvolti nell’assunzione di cibo e nel controllo di importanti steps del metabolismo periferico. Inoltre, cercheremo di fornire solidità scientifica alla teoria che propone tra le cause predisponenti dell’obesità la sovrastimolazione patologica del sistema endocannabinoide. Infine, commenteremo le recenti sperimentazioni nell’uomo per il trattamento dell’obesità e delle sue complicanze metaboliche di una nuova classe di farmaci ad azione bloccante il recettore di tipo 1 dei cannabinoidi, una nuova frontiera nel trattamento di questa temibile patologia.