Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism

FASEB J. 2010 Dec;24(12):4948-59. doi: 10.1096/fj.10-164921. Epub 2010 Aug 19.


Recent studies showed that germ-free (GF) mice are resistant to obesity when consuming a high-fat, high-carbohydrate Western diet. However, it remains unclear what mechanisms are involved in the antiobesity phenotype and whether GF mice develop insulin resistance and dyslipidemia with high-fat (HF) feeding. In the present study, we compared the metabolic consequences of HF feeding on GF and conventional (conv) C57BL/6J mice. GF mice consumed fewer calories, excreted more fecal lipids, and weighed significantly less than conv mice. GF/HF animals also showed enhanced insulin sensitivity with improved glucose tolerance, reduced fasting and nonfasting insulinemia, and increased phospho-Akt((Ser-473)) in adipose tissue. In association with enhanced insulin sensitivity, GF/HF mice had reduced plasma TNF-α and total serum amyloid A concentrations. Reduced hypercholesterolemia, a moderate accretion of hepatic cholesterol, and an increase in fecal cholesterol excretion suggest an altered cholesterol metabolism in GF/HF mice. Pronounced nucleus SREBP2 proteins and up-regulation of cholesterol biosynthesis genes indicate that enhanced cholesterol biosynthesis contributed to the cholesterol homeostasis in GF/HF mice. Our results demonstrate that fewer calorie consumption and increased lipid excretion contributed to the obesity-resistant phenotype of GF/HF mice and reveal that insulin sensitivity and cholesterol metabolism are metabolic targets influenced by the gut microbiota.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Body Weight / physiology
  • Cholesterol / metabolism*
  • Dietary Fats / adverse effects*
  • Germ-Free Life
  • Glucose Tolerance Test
  • Glycogen / metabolism
  • Insulin Resistance / physiology*
  • Lipids / blood
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / blood
  • Obesity / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Polymerase Chain Reaction


  • Dietary Fats
  • Lipids
  • Glycogen
  • Cholesterol