Adipose tissue selective insulin receptor knockout protects against obesity and obesity-related glucose intolerance.
Insulin signaling in adipose tissue plays an important role in lipid storage and regulation of glucose homeostasis. Using the Cre-loxP system, we created mice with fat-specific disruption of the insulin receptor gene (FIRKO mice). These mice have low fat mass, loss of the normal relationship between plasma leptin and body weight, and are protected against age-related and hypothalamic lesion-induced obesity, and obesity-related glucose intolerance. FIRKO mice also exhibit polarization of adipocytes into populations of large and small cells, which differ in expression of fatty acid synthase, C/EBP alpha, and SREBP-1. Thus, insulin signaling in adipocytes is critical for development of obesity and its associated metabolic abnormalities, and abrogation of insulin signaling in fat unmasks a heterogeneity in adipocyte response in terms of gene expression and triglyceride storage.
Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, MA 02215, USA.
Matthias
M
Blüher
M Dodson
MD
Michael
Odile D
OD
Peroni
Kohjiro
K
Ueki
Nathan
N
Carter
Barbara B
BB
Kahn
C Ronald
CR
Kahn
D017667:Adipocytes / Q000378:metabolism*; D052242:Adiponectin; D000273:Adipose Tissue / Q000378:metabolism* / Q000503:physiopathology; D000818:Animals; D006051:Aurothioglucose / Q000494:pharmacology; D001835:Body Weight / Q000235:genetics; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D048429:Cell Size / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004734:Energy Metabolism / Q000235:genetics; D005260:Female; D005947:Glucose / Q000378:metabolism; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009004:Monosaccharide Transport Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins; D009765:Obesity / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011972:Receptor, Insulin / Q000172:deficiency* / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
D052242:Adiponectin; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D011506:Proteins; C495693:Slc2a4 protein, mouse; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D006051:Aurothioglucose; D011972:Receptor, Insulin; D005947:Glucose