acute overactive endocannabinoid signaling induces glucose intolerance, hepatic steatosis, and novel cannabinoid receptor 1 responsive genes急性过于活跃的神经信号诱导葡萄糖耐受不良,肝脂肪变性,新颖的大麻素受体1响应基因.pdfVIP

Acute Overactive Endocannabinoid Signaling Induces Glucose Intolerance, Hepatic Steatosis, and Novel Cannabinoid Receptor 1 Responsive Genes 1 2 2 1 2 Maxwell A. Ruby , Daniel K. Nomura , Carolyn S. S. Hudak , Anne Barber , John E. Casida , Ronald M. Krauss1* 1 Department of Atherosclerosis Research, Children’s Hospital Oakland Research Institute, Oakland, California, United States of America, 2 Department of Nutritional Sciences and Toxicology, University of California, Berkeley, California, United States of America Abstract Endocannabinoids regulate energy balance and lipid metabolism by stimulating the cannabinoid receptor type 1 (CB1). Genetic deletion and pharmacological antagonism have shown that CB1 signaling is necessary for the development of obesity and related metabolic disturbances. However, the sufficiency of endogenously produced endocannabinoids to cause hepatic lipid accumulation and insulin resistance, independent of food intake, has not been demonstrated. Here, we show that a single administration of isopropyl dodecylfluorophosphonate (IDFP), perhaps the most potent pharmacological inhibitor of endocannabinoid degradation, increases hepatic triglycerides (TG) and induces insulin resistance in mice. These effects involve increased CB1 signaling, as they are mitigated by pre-administration of a CB1 antagonist (AM251) and in CB1 knockout mice. Despite the strong physiological effects of CB1 on hepatic lipid and glucose metabolism, little is known about the downstream targets responsible for these effects. To elucidate transcriptional targets of CB1 signaling, we performed microarrays on hepatic RNA isolated from DMSO (control), IDFP and AM251/IDFP-treated mice. The gen