Central Endocannabinoid Signaling Regulates Hepatic Glucose Production and Systemic Lipolysis

OBJECTIVE The endocannabinoid (EC) system has been implicated as an important regulator of energy homeostasis. In obesity and type 2 diabetes, EC tone is elevated in peripheral tissues including liver, muscle, fat, and also centrally, particularly in the hypothalamus. Cannabinoid receptor type 1 (CB₁) blockade with the centrally and peripherally acting rimonabant induces weight loss and improves glucose homeostasis while also causing psychiatric adverse effects. The relative contributions of peripheral versus central EC signaling on glucose homeostasis remain to be elucidated. The aim of this study was to test whether the central EC system regulates systemic glucose fluxes. RESEARCH DESIGN AND METHODS We determined glucose and lipid fluxes in male Sprague-Dawley rats during intracerebroventricular infusions of either WIN55,212-2 (WIN) or arachidonoyl-2'-chloroethylamide (ACEA) while controlling circulating insulin and glucose levels through hyperinsulinemic, euglycemic clamp studies. Conversely, we fed rats a high-fat diet for 3 days and then blocked central EC signaling with an intracerebroventricular infusion of rimonabant while assessing glucose fluxes during a clamp. RESULTS Central CB₁ activation is sufficient to impair glucose homeostasis. Either WIN or ACEA infusions acutely impaired insulin action in both liver and adipose tissue. Conversely, in a model of overfeeding-induced insulin resistance, CB₁ antagonism restored hepatic insulin sensitivity. CONCLUSIONS Thus central EC tone plays an important role in regulating hepatic and adipose tissue insulin action. These results indicate that peripherally restricted CB₁ antagonists, which may lack psychiatric side effects, are also likely to be less effective than brain-permeable CB₁ antagonists in ameliorating insulin resistance.