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

• Published in: The Journal of biological chemistry 2001-02, Vol.276 (8), p.5629-5635
• Main Authors: Lee, Y, Wang, M Y, Kakuma, T, Wang, Z W, Babcock, E, McCorkle, K, Higa, M, Zhou, Y T, Unger, R H
• Format: Article
• Language: English
• Subjects: Animals; Body Composition; Carnitine O-Palmitoyltransferase - genetics; Carnitine O-Palmitoyltransferase - metabolism; Carrier Proteins - genetics; Diet; Dietary Fats - metabolism; Energy Intake; Fatty Acids - metabolism; Fatty Acids, Nonesterified - blood; Gene Expression Regulation; Glucose - metabolism; Hypothalamus - metabolism; Islets of Langerhans - pathology; Leptin - blood; Liver - metabolism; Mutation; Obesity - etiology; Obesity - metabolism; Rats; Rats, Sprague-Dawley; Rats, Zucker; Receptors, Cell Surface; Receptors, Cytoplasmic and Nuclear - genetics; Receptors, Cytoplasmic and Nuclear - metabolism; Receptors, Leptin; Transcription Factors - genetics; Transcription Factors - metabolism; Triglycerides - metabolism
• ISSN: 0021-9258
• DOI: 10.1074/jbc.M008553200

To test the hypothesis that the physiologic liporegulatory role of hyperleptinemia is to prevent steatosis during caloric excess, we induced obesity by 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 approximately 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 antisteatotic activity. In rodents without leptin action (fa/fa rats and ob/ob and db/db mice) receiving a 6% fat diet, nonadipose tissue TG was 4-100 times normal. In normal rats on a 60% fat diet, peroxisome proliferator-activated receptor alpha protein and liver-carnitine palmitoyltransferase-1 (l-CPT-1) mRNA increased in liver. In their pancreatic islets, fatty-acid oxidation increased 30% without detectable increase in the expression of peroxisome proliferator-activated receptor-alpha or oxidative enzymes, whereas lipogenesis from [14C]glucose was slightly below that of the 4% fat-fed rats (p < 0.05). Tissue-specific overexpression of wild-type leptin receptors in the livers of fa/fa rats, in which marked steatosis is uniformly present, reduced TG accumulation in liver but nowhere 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 oxidation.