Liporegulation in diet-induced obesity - The antisteatotic role of hyperleptinemia

To test the hypothesis that the physiologic liporegulatory role of hyperlep tinemia is to prevent steatosis during caloric excess, we induced obesity b y feeding normal Harlan Sprague-Dawley rats a 60% fat diet. Hyperleptinemia began within 24 h and increased progressively to 26 ng/ml after 10 weeks, correlating with an similar to 150-fold increase in body fat (r = 0.91, p < 0.0001). During this time, the triacylglycerol (TG) content of nonadipose tissues rose only 1-2.7-fold implying anti-steatotic activity. In rodents w ithout leptin action (fa/fa rats and ob/ob and db/db mice) receiving a 6% f at diet, nonadipose tissue TG was 4-100 times normal. In normal rats on a 6 0% fat diet, peroxisome proliferator-activated receptor cu protein and live r-carnitine palmitoyl-transferase-1 (L-CPT-1) mRNA increased in liver. In t heir pancreatic islets, fatty-acid oxidation increased 30% without detectab le increase in the expression of peroxisome proliferator-activated receptor -cy or oxidative enzymes, whereas lipogenesis from [C-14]glucose was slight ly below that of the 4% fat-fed rats (p < 0.05). Tissue-specific overexpres sion of wild-type leptin receptors in the livers of fa/fa rats, in which ma rked steatosis is uniformly present, reduced TG accumulation in liver but n owhere else. We conclude that a physiologic role of the hyperleptinemia of caloric excess is to protect nonadipocytes from steatosis and lipotoxicity by preventing the up-regulation of lipogenesis and increasing fatty-acid ox idation.