TY - JOUR
T1 - Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity
AU - Tam, Joseph
AU - Godlewski, Grzegorz
AU - Earley, Brian J.
AU - Zhou, Liang
AU - Jourdan, Tony
AU - Szanda, Gergö
AU - Cinar, Resat
AU - Kunos, George
PY - 2014/2/15
Y1 - 2014/2/15
N2 - The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type 1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist rimonabant in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo-/-) mice and their wild-type littermate controls (Adipo+/+). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo+/+ and Adipo-/- mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin.
AB - The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type 1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist rimonabant in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo-/-) mice and their wild-type littermate controls (Adipo+/+). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo+/+ and Adipo-/- mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin.
KW - Cannabinoid type 1 antagonism
KW - Fatty acid uptake
KW - Hepatic steatosis and fibrosis
KW - Insulin resistance
UR - http://www.scopus.com/inward/record.url?scp=84894031718&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00489.2013
DO - 10.1152/ajpendo.00489.2013
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C2 - 24381003
AN - SCOPUS:84894031718
SN - 0193-1849
VL - 306
SP - E457-E468
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 4
ER -