Leptin dose-dependently decreases atherosclerosis by attenuation of hypercholesterolemia and induction of adiponectin

Objectives: Conflicting evidence concerning leptin in atherosclerosis has been published. Furthermore, dose-dependent effects of leptin on atherogenesis have not been studied. Methods: Leptin-deficient low-density lipoprotein receptor (LDLR) knockout (LDLR-/-;ob/ob) mice were treated with saline, 0.1, 0.5, or 3.0 mg/kg body weight (BW)/d recombinant leptin over 12 weeks starting at 8 weeks of age. Aortic root and brachiocephalic artery (BCA) atherosclerotic lesions were analyzed by oil red 0 staining. Furthermore, glucose homeostasis, lipid metabolism, and liver function including tissue studies were assessed in all animals. Results: Leptin treatment dose-dependently decreased BW in LDLR-/-;ob/ob mice as compared to saline. Mice in the 0.1 and 0.5 mg/kg BW/d groups remained heavier (i.e. subphysiological leptin dose) and in the 3.0 mg/kg BW/d group had similar weight (i.e. physiological leptin dose) as compared to non-leptin-deficient LDLR-/- animals. Recombinant leptin dose-dependently reduced plaque area in the aortic root and the BCA by 36% and 58%, respectively. Leptin-mediated reductions of plasma total and LDL-cholesterol (Chol) remained independent predictors for aortic root plaque area. Chol content in liver, as well as hepatic expression of key lipid and proinflammatory genes, were dose-dependently regulated by leptin. Furthermore, leptin treatment increased circulating levels and adipose tissue mRNA expression of the adipokine adiponectin. Conclusions: Leptin administration within the subphysiological to physiological range diminishes atherosclerotic lesions. Leptin appears to mediate its antiatherogenic effects indirectly through reduction of hyper-cholesterolemia and liver steatosis, as well as upregulation of insulin-sensitizing and atheroprotective adiponectin. (C) 2015 Published by Elsevier B.V.