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

Rabot, Sylvie; Membrez, Mathieu; Bruneau, Aurélia; Gérard, Philippe; Harach, Taoufiq; Moser, Mireille; Raymond, Frédéric; Mansourian, Robert; Chou, Chieh Jason

doi:10.1096/fj.10.164921

Cited by 121 publications

(135 citation statements)

References 42 publications

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“…Interestingly, FIAF transgenic mice also exhibit increases in circulating triglycerides and cholesterol, similar to a nonfeeding state (1,2,14). We found that, despite maintaining similar adiposity, GF rats had increased circulating triglycerides and cholesterol, similar to previous results (1,9,15). Finally, GF mice had decreased blood glucose levels (1,2,8), similar to the nonfeeding state, which is most likely due to decreases in intestinal glucose absorption (1).…”

Section: Intestinal Vs Adipose Fiaf Expression and Adiposity In Gf Asupporting

confidence: 84%

“…The GF status generally is associated with decreased energy extraction from the diet, due to lack of intestinal microbial fermentation resulting in increased fecal energy (1,2,4,9,10). Food intake in GF animals, however, is increased or unchanged during chow feeding and decreased or unchanged during obesogenic or HF feeding (1,2,4,9,10).…”

Section: Alterations In Gut Peptides and Intestinal Gpr Content In Gfmentioning

confidence: 99%

“…The GF state is also characterized by increased fatty acid oxidation and inhibition of lipogenesis due to chronically low adiposity observed in these animals (1,2,4,9). The main mechanism of decreased de novo lipogenesis is thought to involve fasting-induced adipocyte factor (FIAF), an inhibitor of lipoprotein lipase (LPL) that is produced in the intestinal epithelium (1,2).…”

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confidence: 99%

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Preserved adiposity in the Fischer 344 rat devoid of gut microbiota

et al. 2013

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The gut microbiota is implicated in host metabolism and energy regulation. Germ-free (GF) C57BL/6 mice display decreased adiposity, an effect associated with increased intestinal fasting-induced adipose factor (FIAF) and decreased hepatic lipogenesis. However, whether the altered metabolism observed in the absence of gut microbiota extends to other species, commonly used to examine energy metabolism, is unknown. Thus, we used the GF Fischer 344 rat to examine adiposity and associated alterations in intestinal nutrient chemoreceptors, gut peptide levels, and FIAF expression, as well as markers of hepatic and adipose lipogenesis and adipogenesis. We found that GF rats displayed similar body weights and adiposity relative to controls. GF state was associated with up-regulation of intestinal and hepatic FIAF, decreased expression of hepatic FAS, ACC-1, and SREBP, and increased pAMPK and pACC. However, GF rats displayed reduced adipocyte FIAF, increased lipogenic enzymes, and decreased pAMPK, accompanied by an increase in adipocyte size. These findings show that, despite increased intestinal FIAF and reduced hepatic lipogenesis, adiposity is preserved in the Fisher 344 GF rat, unlike the C57Bl/6J GF mouse, with a shift in increased adipocyte lipogenesis. This also demonstrates that adipose, rather than intestinal, FIAF may have a more prominent role in adiposity.

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Section: Intestinal Vs Adipose Fiaf Expression and Adiposity In Gf Asupporting

confidence: 84%

Section: Alterations In Gut Peptides and Intestinal Gpr Content In Gfmentioning

confidence: 99%

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confidence: 99%

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Preserved adiposity in the Fischer 344 rat devoid of gut microbiota

et al. 2013

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“…We then tested the effects of feeding a high-fat diet to klotho-knockout mice and have determined specific changes in body weight and fat accumulation, along with morphological changes of the liver (12,20,21). Remarkably, there was no body weight gain during high-fat-diet feeding compared with normal-fat-diet-fed klotho-knockout mice; that is, klotho-knockout mice did not present with dietary fat-induced obesity.…”

Section: Discussionmentioning

confidence: 99%

Dietary and genetic evidence for enhancing glucose metabolism and reducing obesity by inhibiting klotho functions

et al. 2011

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Klotho is a multifunctional protein involved in numerous biological functions, ranging from mineral ion metabolism to signaling activities. Recent studies have identified klotho as a target gene for peroxisome proliferator-activated receptor-γ (PPAR-γ), a master regulator of adipocyte differentiation, and an adipogenesis-promoting factor. In a similar line of observation, eliminating klotho function from mice resulted in the generation of lean mice with almost no detectable fat tissue. In contrast to the klotho-knockout mice (11.7±0.3 g at 9 wk), leptin-deficient (ob/ob) mice are severely obese (49.3±0.6 g at 9 wk), due to excessive fat accumulation. To study the in vivo role of klotho in obesity, we have generated and characterized ob/ob mice lacking klotho activity [ob/ob-klotho double-knockout (DKO) mice]. The ob/ob mice started to get bigger from 3 wk onward and gained almost 2 times more weight than their wild-type (WT) counterparts (WT vs. ob/ob: 34.8±1.3 vs. 65.5±1.2 g at 21 wk). The generated ob/ob-klotho DKO mice were not only viable throughout their adulthood but also showed markedly reduced fat tissue accumulation compared to their ob/ob littermates. The ob/ob-klotho DKO mice had significantly (P<0.01) less retroperitoneal, mesenteric, and epididymal fat accumulation, compared to their ob/ob counterparts. Similarly, the fatty liver that was consistently observed in the ob/ob mice was eliminated in the ob/ob-klotho DKO mice. Such structural improvement in the liver was also evident from markedly reduced fasting blood glucose levels in ob/ob-klotho DKO mice, compared to their ob/ob counterparts (ob/ob vs. ob/ob-klotho DKO: 266 ± 36 vs. 65±2 mg/dl). Finally, to study whether the absence of klotho can induce resistance to high-fat-diet-induced obesity, we provided a high-fat (60%) diet to klotho-knockout mice and compared them with normal-fat (20%) diet-fed klotho-knockout mice. No significant difference in body weight was detected in klotho-knockout mice fed either the normal-fat diet or high-fat diet, while WT mice fed the high-fat diet gradually gained body weight, compared to the normal-fat-diet-fed counterparts. The results of our dietary and genetic manipulation studies provide in vivo evidence for a role of klotho in obesity and offer a novel target to manipulate obesity and associated complications.

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“…High SAA levels lower insulin sensitivity in adipocytes (71) and may therefore explain the insulin resistance observed in conventionalization studies (70,72,73). In addition, fasting plasma free fatty acid levels have been found to be higher in conventionally raised mice (70), also potentially contributing to insulin resistance (74). Membrez et al (75) reported that, in 2 different mouse models of insulin resistance, treatment with norfloxacin and ampicillin lowered fasting and post-glucose tolerance test glucose and insulin plasma levels.…”

Section: Causal Link Between Gut Microbiota and Metabolic Healthmentioning

confidence: 99%

The role of the gut microbiota in metabolic health

2015

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The global prevalence of obesity and related comorbidities has increased considerably over the past decades. In addition to an increase in food consumption and a reduction in physical activity, growing evidence implicates the microorganisms in our gastrointestinal tract, referred to as the gut microbiota, in obesity and related metabolic disturbances. The composition of the gut microbiota can fluctuate markedly within an individual and between individuals. Changes in gut microbial composition may be unfavorable and predispose an individual to disease. Studies in mice that are germ free, mice that are cohoused, and mice that are treated with antibiotics have provided some evidence that changes in gut microbiota may causally contribute to metabolic disorders. Several mechanisms have been proposed and explored that may mediate the effects of the gut microbiota on metabolic disorders. In this review, we carefully analyze the literature on the connection between the gut microbiota and metabolic health, with a focus on studies demonstrating a causal relation and clarifying potential underlying mechanisms. Despite a growing appreciation for a role of the gut microbiota in metabolic health, more experimental evidence is needed to substantiate a cause-and-effect relationship. If a clear causal relationship between the gut microbiota and metabolic health can be established, dietary interventions can be targeted toward improving gut microbial composition in the prevention and perhaps even the treatment of metabolic diseases.

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

Cited by 121 publications

References 42 publications

Preserved adiposity in the Fischer 344 rat devoid of gut microbiota

Preserved adiposity in the Fischer 344 rat devoid of gut microbiota

Dietary and genetic evidence for enhancing glucose metabolism and reducing obesity by inhibiting klotho functions

The role of the gut microbiota in metabolic health

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