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

Abstract

A combination of central and peripheral mechanisms modulates food intake and energy consumption to maintain metabolism and body composition in mammals. Diseases characterized by impaired energy balance, such as obesity, rank among the most immediate health threats in industrialized countries, creating an urgent need to generate new pharmacologic treatment options (1, 2). The discovery of leptin has triggered intensified research efforts in the field of energy homeostasis, leading to a better understanding of a complex network of central and peripheral factors that influence both appetite and energy expenditure (3).The discovery of cannabinoid receptor type 1 (CB1) and cannabinoid receptro type 2 (CB2), provided a molecular basis for investigating the effects 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 prepro-orexin, 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.

Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids

“…When assessing the evolution of MS, we have seen that patients, who became free of MS at follow-up, had lower baseline caloric intake with particularly lower consumption of SFA than subjects without MS resolution. This is in line with studies showing the involvement of dietary SFA in the development of cardiovascular diseases and supporting the current dietary recommendations to reduce the intake of SFA [8,37]. However, data showing relation between SFA intake and MS are scarce and surprisingly controversial, with some reports showing no effect of dietary SFA on chronic diseases [39].…”

“…The endocannabinoids play an important role in the control of food intake, energy balance, and reward mechanisms [8,9,10]. We have recently shown that plasma N-palmitoylethanolamide (PEA) is correlated with coronary function which could be a functional precursor of coronary heart disease in obesity [11].…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…increased energy expenditure) mechanisms (Cota et al ., 2003; Jbilo et al ., 2005; Herling et al ., 2008; Nogueiras et al ., 2008). Whilst this present study did not permit us to discriminate between these two different modes of action directly, our findings indicate that rimonabant is unlikely to convey its metabolic improvements in aged mice by increasing energy expenditure.…”

Effects of a High-Protein/Low-Carbohydrate versus a Standard Hypocaloric Diet on Weight and Cardiovascular Risk Factors during 9 Months: Role of a Genetic Variation in the Cannabinoid Receptor Gene (CNR1) (G1359A Polymorphism)

“…Previous investigations support the notion that endocannabinoid system is positioned for the regulation of endocannabinoid levels that could influence craving and reward behaviors through the relevant neuronal circuitry and metabolic parameters [22]. Novel peripheral mechanisms of action have been attributed to the endocannabinoid system through its ability to directly target adipocytes [23] and skeletal muscle [24]. And finally, the potential relation of this SNP with metabolic syndrome is other interesting area to evaluate [25].…”