Fat storage in adipocytes requires inactivation of leptin's paracrine activity: implications for treatment of human obesity.
Hyperleptinemia rapidly depletes adipocyte fat in lean rats, whereas comparable hyperleptinemia produced by adipocytes in diet-induced obesity does not, implying a leptinergic blockade in adipocytes during overnutrition. Indeed, activated STAT-3 in white adipose tissue (WAT) of normal rats was less on a 60% high fat diet (HFD) than on 4% fat, despite a 10-fold higher plasma leptin. In 6 days of a HFD, mRNA of the postreceptor leptin inhibitor, suppressor of cytokine signaling-3, increased 22-fold in WAT, while leptin receptor (Lepr-b) mRNA gradually disappeared, implying leptinergic blockade at both postreceptor and receptor levels. Adipocyte-specific Lepr-b overexpression of a Lepr-b transgene completely prevented the adipocyte hypertrophy and hyperplasia and the increase in body fat induced in wild-type mice by HFD. Activated STAT-3 and AMP-activated protein kinase (AMPK), and the mRNA of lipooxidative enzymes, peroxisome proliferator-activated receptor-gamma-coactivator-1alpha, and uncoupling protein-1 and -2 were increased in WAT. Body temperature was elevated in the transgenic mice, suggesting uncoupled fatty acid oxidation of surplus fatty acids. In conclusion, storage of surplus calories in WAT and the development of diet-induced obesity require the blockade of a latent leptin-stimulated caloric sump in white adipocytes.
Wang
May-Yun
MY
Gifford Laboratories, Touchstone Center for Diabetes Research and Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, 75390-8854, USA.
Orci
Lelio
L
Ravazzola
Mariella
M
Unger
Roger H
RH
D000263:Adenylate Kinase / Q000378:metabolism; D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D004041:Dietary Fats / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D015151:Immunoblotting; D007473:Ion Channels; D020738:Leptin / Q000097:blood / Q000378:metabolism*; D050356:Lipid Metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D019899:Paracrine Communication / Q000187:drug effects* / Q000502:physiology; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D054411:Receptors, Leptin; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D019076:Transgenes / Q000235:genetics; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2
D002352:Carrier Proteins; D004041:Dietary Fats; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C000604371:UCP1 protein, human; C000604372:Ucp1 protein, mouse; C000604373:Ucp1 protein, rat; D000071256:Uncoupling Protein 1; D000071246:Uncoupling Protein 2; D000263:Adenylate Kinase