Requirement of cannabinoid receptor type 1 for the basal modulation of hypothalamic-pituitary-adrenal axis function.

The endocannabinoid system affects the neuroendocrine regulation of hormone secretion, including the activity of the hypothalamus-pituitary-adrenal (HPA) axis. However, the mechanisms by which endocannabinoids regulate HPA axis function have remained unclear. Here we demonstrate that mice lacking cannabinoid receptor type 1 (CB1-/-) display a significant dysregulation of the HPA axis. Although circadian HPA axis responsiveness is preserved, CB1-/- mice are characterized by an enhanced circadian drive on the HPA axis, resulting in elevated plasma corticosterone concentrations at the onset of the dark as compared with wild-type (CB1+/+) littermates. Moreover, CB1-/--derived pituitary cells respond with a significantly higher ACTH secretion to CRH and forskolin challenges as compared with pituitary cells derived from CB1+/+ mice. Both CBL-/- and CB1+/+ mice properly respond to a high-dose dexamethasone test, but response to low-dose dexamethasone is influenced by genotype. In addition, CB1-/- mice show increased CRH mRNA levels in the paraventricular nucleus of the hypothalamus but not in other extrahypothalamic areas, such as the amygdala and piriform cortex, in which CB1 and CRH mRNA have been colocalized. Finally, CB1-/- mice have selective glucocorticoid receptor mRNA down-regulation in the CA1 region of the hippocampus but not in the dentate gyrus or paraventricular nucleus. Conversely, mineralocorticoid receptor mRNA expression levels were found unchanged in these brain areas. In conclusion, our findings indicate that CB1 deficiency enhances the circadian HPA axis activity peak and leads to central impairment of glucocorticoid feedback, thus further outlining the essential role of the endocannabinoid system in the modulation of neuroendocrine functions.

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.