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

TLDR

Recent studies show that germ‑free mice are resistant to obesity when fed a high‑fat, high‑carbohydrate Western diet. The study aimed to determine the mechanisms underlying this anti‑obesity phenotype and whether germ‑free mice develop insulin resistance and dyslipidemia with high‑fat feeding. Researchers compared the metabolic effects of a high‑fat diet on germ‑free versus conventional C57BL/6J mice. GF mice on the high‑fat diet ate fewer calories, excreted more lipids, weighed less, exhibited enhanced insulin sensitivity and improved glucose tolerance, lower inflammatory markers, and altered cholesterol metabolism—reduced hypercholesterolemia, increased fecal cholesterol excretion, and up‑regulated cholesterol‑biosynthesis genes—demonstrating that gut microbiota influence obesity resistance, insulin sensitivity, and cholesterol homeostasis.

Abstract

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.