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Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.

ABSTRACT: Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) diet of more than 100 inbred strains of mice. Here we show that HF/HS feeding promotes robust, strain-specific changes in obesity that are not accounted for by food intake and provide evidence for a genetically determined set point for obesity. GWAS analysis identified 11 genome-wide significant loci associated with obesity traits, several of which overlap with loci identified in human studies. We also show strong relationships between genotype and gut microbiota plasticity during HF/HS feeding and identify gut microbial phylotypes associated with obesity.

SUBMITTER: Parks BW

PROVIDER: S-EPMC3545283 | biostudies-other | 2013 Jan

REPOSITORIES: biostudies-other

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Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.

Parks Brian W BW Nam Elizabeth E Org Elin E Org Elin E Kostem Emrah E Norheim Frode F Hui Simon T ST Pan Calvin C Civelek Mete M Rau Christoph D CD Bennett Brian J BJ Mehrabian Margarete M Ursell Luke K LK He Aiqing A Castellani Lawrence W LW Zinker Bradley B Kirby Mark M Drake Thomas A TA Drevon Christian A CA Knight Rob R Gargalovic Peter P Kirchgessner Todd T Eskin Eleazar E Lusis Aldons J AJ

Cell metabolism 20130101 1

Obesity is a highly heritable disease driven by complex interactions between genetic and environmental factors. Human genome-wide association studies (GWAS) have identified a number of loci contributing to obesity; however, a major limitation of these studies is the inability to assess environmental interactions common to obesity. Using a systems genetics approach, we measured obesity traits, global gene expression, and gut microbiota composition in response to a high-fat/high-sucrose (HF/HS) di ...[more]

PMID: 23312289

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Project description:Background: Accumulating data support the fact that the gut microbiota plays an important role in the progression of obesity and its related metabolic disease. Sex-related differences are an important consideration in the study of gut microbiota. Polyphenols can regulate gut microbiota, thereby improving obesity and its associated complications. There have been no studies conducted on the ability of honokiol (HON, an extract from Chinese herbal medicine) to regulate gut microbiota. The aim of this study was to examine whether HON supplementation would improve obesity by regulating the gut microbiota and its related metabolite levels, and whether there were sex-based differences in high-fat diet-induced obese mice. Methods: C57BL/6 mice (n = 120) were fed a normal chow diet (ND group), high-fat diet (HFD group), or HFD plus HON at 200, 400, and 800 mg/kg BW for 8 weeks. Body weight, adipose tissue weight, adipocyte diameter, insulin resistance, blood lipid and serum inflammatory cytokines, gut microbiota, and its metabolite were examined at the end of the experiment. Results: The HON supplementation reduced body weight, adipose tissue weight, adipocyte diameter, insulin resistance, blood lipid, and serum inflammatory cytokine levels in HFD-fed mice, and this effect was significant in the high-dose group. In addition, HON not only reversed gut disorders in HFD-fed mice, such as by enhanced the abundance of Akkermansia and short-chain fatty acids (SCFAs) producing Bacteroides and reduced Oscillospira, but also improved the SCFAs and endotoxin (LPS) levels, although there were sex-based differences. The correlation between several specific genera and obesity-related indexes was revealed through Spearman's correlation analysis. Moreover, HON may have dose-dependent effects on regulating gut microbiota to alleviate obesity. Conclusions: These findings suggest that HON can prevent diet-induced obesity and its associated diseases by regulating the gut microbiota and improving microbial metabolite levels. Moreover, our findings indicate that sex may be an important factor affecting HON activity.

Project description:ObjectiveGut microbiota may promote positive energy balance; however, germfree mice can be either resistant or susceptible to diet-induced obesity (DIO) depending on the type of dietary intervention. We here sought to identify the dietary constituents that determine the susceptibility to body fat accretion in germfree (GF) mice.MethodsGF and specific pathogen free (SPF) male C57BL/6N mice were fed high-fat diets either based on lard or palm oil for 4 wks. Mice were metabolically characterized at the end of the feeding trial. FT-ICR-MS and UPLC-TOF-MS were used for cecal as well as hepatic metabolite profiling and cecal bile acids quantification, respectively. Hepatic gene expression was examined by qRT-PCR and cecal gut microbiota of SPF mice was analyzed by high-throughput 16S rRNA gene sequencing.ResultsGF mice, but not SPF mice, were completely DIO resistant when fed a cholesterol-rich lard-based high-fat diet, whereas on a cholesterol-free palm oil-based high-fat diet, DIO was independent of gut microbiota. In GF lard-fed mice, DIO resistance was conveyed by increased energy expenditure, preferential carbohydrate oxidation, and increased fecal fat and energy excretion. Cecal metabolite profiling revealed a shift in bile acid and steroid metabolites in these lean mice, with a significant rise in 17β-estradiol, which is known to stimulate energy expenditure and interfere with bile acid metabolism. Decreased cecal bile acid levels were associated with decreased hepatic expression of genes involved in bile acid synthesis. These metabolic adaptations were largely attenuated in GF mice fed the palm-oil based high-fat diet. We propose that an interaction of gut microbiota and cholesterol metabolism is essential for fat accretion in normal SPF mice fed cholesterol-rich lard as the main dietary fat source. This is supported by a positive correlation between bile acid levels and specific bacteria of the order Clostridiales (phylum Firmicutes) as a characteristic feature of normal SPF mice fed lard.ConclusionsIn conclusion, our study identified dietary cholesterol as a candidate ingredient affecting the crosstalk between gut microbiota and host metabolism.

Dataset Information

Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.

Publications

Genetic control of obesity and gut microbiota composition in response to high-fat, high-sucrose diet in mice.

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