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

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.

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

“…The nuclear receptor cofactor and master regulator of mitochondrial biogenesis PPARGC1A binds HNF4A and promotes activation of HNF4A target genes (Rha et al 2009). Colonization of GF animals with microbiota leads to increased energy harvest (Rabot et al 2010;Semova et al 2012) and changes in metabolic homeostasis including decreased AMPK complex activity in skeletal muscle and liver (Backhed et al 2007). Previous studies have also shown that the activated AMPK complex phosphorylates and activates PPARGC1A (Jager et al 2007); therefore, microbiota might suppress HNF4A activity indirectly through induced alterations in metabolic homeostasis.…”

Nonalcoholic fatty pancreas disease as an endogenous alcoholic fatty pancreas disease

“…This key role of gut microbiota in FPM of ethanol is supported by studies showing that oral antibiotics protect against both NAFLD/NAFPD [130][131][132][133][134] and alcoholic liver disease [135]. Furthermore, germ-free animals are also protected against dietinduced obesity-related disorders [136][137][138] as well as ethanol-induced liver injury [139].…”

Lipides et inflammation postprandiale : impact du microbiote intestinal

“…De plus, des animaux deficients pour le corecepteur CD14 ne developpent pas de desordres metaboliques sous regimes gras même si les TLR4 et 2 sont exprimes (Cani et al, 2007a ;Roncon-Albuquerque, Jr. et al, 2008). Enfin, des souris axeniques soumises a un regime riche en lipides ne developpent pas d'inflammation de faible grade, ni d'insulino-resistance alors que les lipides sont absorbes et digeres (Rabot et al, 2010). A l'issue de ces observations, nous pouvons proposer qu'une cascade d'evenements inities par des mecanismes dependant du complexe LPS/CD14/TLR4 activeraient l'expression de TLR-2 et par la declencherait une reponse du systeme immunitaire inne en terme inflammatoire (pour revue (Cani et Delzenne, 2011)).…”