Adipose Tissue Selective Insulin Receptor Knockout Protects Against Obesity and Obesity-Related Glucose Intolerance

Dev Cell. 2002 Jul;3(1):25-38. doi: 10.1016/s1534-5807(02)00199-5.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adipocytes / metabolism*
  • Adiponectin
  • Adipose Tissue / metabolism*
  • Adipose Tissue / physiopathology
  • Animals
  • Aurothioglucose / pharmacology
  • Body Weight / genetics
  • CCAAT-Enhancer-Binding Proteins / genetics
  • CCAAT-Enhancer-Binding Proteins / metabolism
  • Cell Size / genetics
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Energy Metabolism / genetics
  • Female
  • Glucose / metabolism
  • Glucose Intolerance / genetics*
  • Glucose Intolerance / metabolism
  • Glucose Intolerance / physiopathology
  • Glucose Transporter Type 1
  • Glucose Transporter Type 4
  • Insulin / metabolism*
  • Intercellular Signaling Peptides and Proteins*
  • Leptin / blood
  • Male
  • Mice
  • Mice, Knockout
  • Monosaccharide Transport Proteins / genetics
  • Monosaccharide Transport Proteins / metabolism
  • Muscle Proteins*
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / physiopathology
  • Proteins / genetics
  • Proteins / metabolism
  • Receptor, Insulin / deficiency*
  • Receptor, Insulin / genetics
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors*
  • Ventromedial Hypothalamic Nucleus / drug effects
  • Ventromedial Hypothalamic Nucleus / pathology
  • Ventromedial Hypothalamic Nucleus / physiopathology

Substances

  • Adiponectin
  • CCAAT-Enhancer-Binding Proteins
  • DNA-Binding Proteins
  • Glucose Transporter Type 1
  • Glucose Transporter Type 4
  • Insulin
  • Intercellular Signaling Peptides and Proteins
  • Leptin
  • Monosaccharide Transport Proteins
  • Muscle Proteins
  • Proteins
  • Slc2a4 protein, mouse
  • Srebf1 protein, mouse
  • Sterol Regulatory Element Binding Protein 1
  • Transcription Factors
  • Aurothioglucose
  • Receptor, Insulin
  • Glucose