title: The role of leptin resistance in the lipid abnormalities of aging.
abstract: Leptin resistance has been implicated in the pathogenesis of obesity-related complications involving abnormalities of lipid metabolism that resemble those of old age. To determine whether development of leptin resistance in advancing age might account for such abnormalities, we compared the effects of hyperleptinemia (>40 ng/ml) induced in 2-month-old and 18-month-old lean wild-type (+/+) Zucker diabetic fatty rats by adenovirus gene transfer. The decline in food intake, body weight, and body fat in old rats was only 25%, 50%, and 16%, respectively, of the young rats. Whereas in young rats plasma free fatty acids fell 44% and triacylglycerol (TG) 94%, neither changed in the rats. In hyperleptinemic young rats, adipocyte expression of preadipocyte factor 1 increased dramatically and leptin mRNA virtually disappeared; there was increased expression of acyl CoA oxidase, carnitine palmitoyl transferase 1, and their transcription factor peroxisome proliferator-activated receptor alpha, accounting for the reduction in body fat. These hyperleptinemia-induced changes were profoundly reduced in the old rats. On a high-fat diet, old rats consumed 28% more calories than the young and gained 1.5x as much fat, despite greater endogenous hyperleptinemia. Expression of a candidate leptin resistance factor, suppressor of cytokine signaling 3 (SOCS-3), was compared in the hypothalamus and white adipocytes of young and old rats before and after induction of hyperleptinemia; hypothalamic SOCS-3 mRNA was approximately 3x higher in old rats before, whereas it was 3x higher in WAT after, hyperleptinemia. We conclude that the anorexic and antilipopenic actions of leptin decline with age, possibly through increased SOCS-3 expression, and that this could account for the associated abnormalities in lipid metabolism of the elderly.
authors.affiliation: Gifford Laboratories, Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Z W
authors.initials: ZW
authors.lastname: Wang
authors.forename: W T
authors.initials: WT
authors.lastname: Pan
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
authors.forename: T
authors.initials: T
authors.lastname: Kakuma
authors.forename: Y T
authors.initials: YT
authors.lastname: Zhou
authors.forename: R H
authors.initials: RH
authors.lastname: Unger
mesh_terms: D042962:Acyl-CoA Oxidase; D000273:Adipose Tissue / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D004351:Drug Resistance; D004790:Enzyme Induction / Q000187:drug effects; D005227:Fatty Acids / Q000378:metabolism; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000008:administration & dosage / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D008565:Membrane Proteins / Q000235:genetics; D010088:Oxidoreductases / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors / Q000235:genetics; D014280:Triglycerides / Q000032:analysis / Q000097:blood; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D004041:Dietary Fats; C512923:Dlk1 protein, rat; D005227:Fatty Acids; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D008565:Membrane Proteins; D011506:Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; C491410:Socs3 protein, rat; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D014157:Transcription Factors; D014280:Triglycerides; D010088:Oxidoreductases; D042962:Acyl-CoA Oxidase; D002334:Carnitine O-Palmitoyltransferase