Genetic Ablation of Lymphocytes and Cytokine Signaling in Nonobese Diabetic Mice Prevents Diet-Induced Obesity and Insulin Resistance

FASEB J. 2016 Mar;30(3):1328-38. doi: 10.1096/fj.15-280610. Epub 2015 Dec 7.

Abstract

Obesity is characterized by a dysregulated immune system, which may causally associate with insulin resistance and type 2 diabetes. Despite widespread use of nonobese diabetic (NOD) mice, NOD with severe combined immunodeficiency (scid) mutation (SCID) mice, and SCID bearing a null mutation in the IL-2 common γ chain receptor (NSG) mice as animal models of human diseases including type 1 diabetes, the underlying metabolic effects of a genetically altered immune system are poorly understood. For this, we performed a comprehensive metabolic characterization of these mice fed chow or after 6 wk of a high-fat diet. We found that NOD mice had ∼50% less fat mass and were 2-fold more insulin sensitive, as measured by hyperinsulinemic-euglycemic clamp, than C57BL/6 wild-type mice. SCID mice were also more insulin sensitive with increased muscle glucose metabolism and resistant to diet-induced obesity due to increased energy expenditure (∼10%) and physical activity (∼40%) as measured by metabolic cages. NSG mice were completely protected from diet-induced obesity and insulin resistance with significant increases in glucose metabolism in peripheral organs. Our findings demonstrate an important role of genetic background, lymphocytes, and cytokine signaling in diet-induced obesity and insulin resistance.

Keywords: diabetes mouse models; energy balance; glucose metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Mellitus, Experimental / metabolism
  • Diabetes Mellitus, Experimental / physiopathology
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / physiopathology
  • Diet, High-Fat / adverse effects
  • Dietary Fats / adverse effects
  • Energy Metabolism / physiology
  • Glucose / metabolism
  • Glucose Clamp Technique / methods
  • Insulin / metabolism
  • Insulin Resistance / physiology*
  • Interleukin-2 / metabolism*
  • Lymphocytes / metabolism*
  • Lymphocytes / physiology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD / metabolism*
  • Mice, Inbred NOD / physiology
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / physiology
  • Obesity / metabolism*
  • Obesity / physiopathology
  • Signal Transduction / physiology

Substances

  • Dietary Fats
  • Insulin
  • Interleukin-2
  • Glucose