title: Liporegulation in diet-induced obesity. The antisteatotic role of hyperleptinemia.
abstract: 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.
authors.affiliation: Gifford Laboratories, Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390-8854, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: M Y
authors.initials: MY
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Kakuma
authors.forename: Z W
authors.initials: ZW
authors.lastname: Wang
authors.forename: E
authors.initials: E
authors.lastname: Babcock
authors.forename: K
authors.initials: K
authors.lastname: McCorkle
authors.forename: M
authors.initials: M
authors.lastname: Higa
authors.forename: Y T
authors.initials: YT
authors.lastname: Zhou
authors.forename: R H
authors.initials: RH
authors.lastname: Unger
mesh_terms: D000818:Animals; D001823:Body Composition; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics; D004032:Diet; D004041:Dietary Fats / Q000378:metabolism; D002149:Energy Intake; D005227:Fatty Acids / Q000378:metabolism; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007515:Islets of Langerhans / Q000473:pathology; D020738:Leptin / Q000097:blood*; D008099:Liver / Q000378:metabolism; D009154:Mutation; D009765:Obesity / Q000209:etiology / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011924:Rats, Zucker; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D004041:Dietary Fats; D005227:Fatty Acids; D005230:Fatty Acids, Nonesterified; D020738:Leptin; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D054411:Receptors, Leptin; D014157:Transcription Factors; D014280:Triglycerides; D002334:Carnitine O-Palmitoyltransferase; D005947:Glucose