Regulation of leptin by agouti.
Dominant mutations at the mouse Agouti locus lead to ectopic expression of the Agouti gene and exhibit diabetes, obesity, and yellow coat color. Obese yellow mice are hyperinsulinemic and hyperleptinemic, and we hypothesized that Agouti directly induces leptin secretion. Accordingly, we used transgenic mice expressing agouti in adipocytes (under the control of aP2 promoter, aP212) to examine changes in leptin levels. Agouti expression in adipose tissue did not significantly alter food intake, weight gain, fat pad weight, or insulinemia; however, the transgenic mice were hyperglycemic. We demonstrated that plasma leptin levels are approximately twofold higher in aP212 transgenic mice compared with their respective controls, whereas ubiquitous expression of agouti (under the control of beta-actin promoter, BAP20) led to a sixfold increase in leptin. Insulin treatment of aP212 mice increased adipocyte leptin content without affecting plasma leptin levels. These findings were further confirmed in vitro in 3T3-L1 adipocytes treated with recombinant Agouti protein and/or insulin. Agouti but not insulin significantly increased leptin secretion, indicating that insulin enhances leptin synthesis but not secretion while Agouti increases both leptin synthesis and secretion. This increased leptin synthesis and secretion was due to increased leptin mRNA levels by Agouti. Interestingly, agouti regulation of leptin was not mediated by melanocortin receptor 4, previously implicated in agouti regulation of food intake. These results suggest that increased leptin secretion by agouti may serve to limit agouti-induced obesity, independent of melanocortin receptor antagonism, and indicate that interaction between obesity genes may play a key role in obesity.
Claycombe
K J
KJ
Department of Nutrition, University of Tennessee, Knoxville, Tennessee 37996, USA.
Xue
B Z
BZ
Mynatt
R L
RL
Zemel
M B
MB
Moustaid-Moussa
N
N
D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D000273:Adipose Tissue / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D054366:Agouti Signaling Protein; D000818:Animals; D002352:Carrier Proteins; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D003920:Diabetes Mellitus / Q000235:genetics; D004334:Drug Administration Schedule; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D006720:Homozygote; D007279:Injections, Subcutaneous; D007328:Insulin / Q000008:administration & dosage; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000032:analysis / Q000097:blood* / Q000235:genetics; D008297:Male; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009765:Obesity; D011401:Promoter Regions, Genetic / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin / Q000819:agonists; D054411:Receptors, Leptin; D044101:Receptors, Melanocortin; D018000:Receptors, Peptide / Q000037:antagonists & inhibitors
D054366:Agouti Signaling Protein; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C082667:Fabp5 protein, mouse; C086936:Fabp7 protein, mouse; D000071438:Fatty Acid-Binding Protein 7; D050556:Fatty Acid-Binding Proteins; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; D012333:RNA, Messenger; D044105:Receptor, Melanocortin, Type 4; D018043:Receptors, Corticotropin; D054411:Receptors, Leptin; D044101:Receptors, Melanocortin; D018000:Receptors, Peptide; C515183:a protein, mouse; C083115:activator protein-2 binding element; C515447:leptin receptor, mouse; C103272:SHU 9119; D009074:Melanocyte-Stimulating Hormones