Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice

Diabetes. 2004 Apr;53(4):931-8. doi: 10.2337/diabetes.53.4.931.

Abstract

The metabolic syndrome (visceral obesity, insulin resistance, type 2 diabetes, and dyslipidemia) resembles Cushing's Syndrome, but without elevated circulating glucocorticoid levels. An emerging concept suggests that the aberrantly elevated levels of the intracellular glucocorticoid reamplifying enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1) found in adipose tissue of obese humans and rodents underlies the phenotypic similarities between idiopathic and "Cushingoid" obesity. Transgenic overexpression of 11 beta-HSD-1 in adipose tissue reproduces a metabolic syndrome in mice, whereas 11 beta-HSD-1 deficiency or inhibition has beneficial metabolic effects, at least on liver metabolism. Here we report novel protective effects of 11 beta-HSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11 beta-HSD-1 nullizygous (11 beta-HSD-1(-/-)) mice. 11 beta-HSD-1(-/-) mice expressed lower resistin and tumor necrosis factor-alpha, but higher peroxisome proliferator-activated receptor-gamma, adiponectin, and uncoupling protein-2 mRNA levels in adipose, indicating insulin sensitization. Isolated 11 beta-HSD-1(-/-) adipocytes exhibited higher basal and insulin-stimulated glucose uptake. 11 beta-HSD-1(-/-) mice also exhibited reduced visceral fat accumulation upon high-fat feeding. High-fat-fed 11 beta-HSD-1(-/-) mice rederived onto the C57BL/6J strain resisted diabetes and weight gain despite consuming more calories. These data provide the first in vivo evidence that adipose 11 beta-HSD-1 deficiency beneficially alters adipose tissue distribution and function, complementing the reported effects of hepatic 11 beta-HSD-1 deficiency or inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / deficiency
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / genetics
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1 / physiology*
  • Adipocytes / drug effects
  • Adipocytes / physiology
  • Adipose Tissue / physiology*
  • Animals
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Body Temperature
  • Body Weight
  • Cholesterol / metabolism
  • Diet
  • Gene Expression Regulation
  • Glucose Tolerance Test
  • Insulin / pharmacology
  • Ion Channels
  • Male
  • Membrane Transport Proteins / genetics
  • Mice
  • Mice, Knockout
  • Mitochondrial Proteins / genetics
  • Obesity / genetics
  • Obesity / prevention & control*
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Transcription Factors / genetics
  • Triglycerides / metabolism
  • Uncoupling Protein 2

Substances

  • Blood Glucose
  • Insulin
  • Ion Channels
  • Membrane Transport Proteins
  • Mitochondrial Proteins
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
  • Triglycerides
  • UCP2 protein, human
  • Ucp2 protein, mouse
  • Uncoupling Protein 2
  • Cholesterol
  • 11-beta-Hydroxysteroid Dehydrogenase Type 1