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Leptin Regulates Peripheral Lipid Metabolism Primarily through Central Effects on Food Intake

University of Cambridge Metabolic Research Laboratories (X.P., Y.C.L.T., I.S.F., S.O'R., A.P.C.), Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom; and Department of Biochemistry (J.L.G.), University of Cambridge, Cambridge CB2 1QW, United Kingdom

Address all correspondence and requests for reprints to: Stephen O'Rahilly or Anthony P. Coll, University of Cambridge Metabolic Research Laboratories, Institute of Metabolic Science, Level 4, Addenbrooke’s Hospital, Box 289, Cambridge CB2 OQQ, United Kingdom. E-mail: so104{at}medschl.cam.ac.uk or apc36{at}cam.ac.uk.

The metabolic effects of leptin may involve both centrally and peripherally mediated actions with a component of the central actions potentially independent of alterations in food intake. Ob/ob mice have significant abnormalities in lipid metabolism, correctable by leptin administration. We used ob/ob mice to study the relative importance of the subtypes of actions of leptin (central vs. peripheral; food intake dependent vs. independent) on lipid metabolism. Mice were treated for 3 d with leptin, either centrally [intracerebroventricular (icv)] or peripherally (ip), and compared with mice pair-fed to the leptin-treated mice (PF) and with ad libitum-fed controls (C). All treatment groups (icv, ip, PF) showed indistinguishable changes in liver weight; hepatic steatosis; hepatic lipidemic profile; and circulating free fatty acids, triglycerides, and cholesterol lipoprotein profile. Changes in the expression of genes involved in lipogenesis and fatty acid oxidation in liver, muscle, and white fat were broadly similar in ip, icv, and PF groups. Leptin (both icv and ip) stimulated expression of both mitochondrial and peroxisomal acyl-coenzyme A oxidase (liver) and peroxisomal proliferator-activated receptor- (skeletal muscle) to an extent not replicated by pair feeding. Leptin had profound effects on peripheral lipid metabolism, but the majority were explained by its effects on food intake. Leptin had additional centrally mediated effects to increase the expression of a limited number of genes concerned with fatty acid oxidation. Whereas we cannot exclude direct peripheral effects of leptin on certain aspects of lipid metabolism, we were unable to detect any such effects on the parameters measured in this study.

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