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CC002/Unc females are mouse models of exercise-induced paradoxical fat response.

ABSTRACT: Exercise results in beneficial health outcomes and protects against a variety of chronic diseases. However, U.S. exercise guidelines recommend identical exercise programs for everyone, despite individual variation in responses to these programs, including paradoxical fat gain. Experimental models of exercise-induced paradoxical outcomes may enable the dissection of underlying physiological mechanisms as well as the evaluation of potential interventions. Whereas several studies have identified individual mice exhibiting paradoxical fat gain following exercise, no systematic effort has been conducted to identify and characterize models of paradoxical response. Strains from the Collaborative Cross (CC) genetic reference population were used due to its high levels of genetic variation, its reproducible nature, and the observation that the CC is a rich source of novel disease models, to assess the impact genetic background has on exercise responses. We identified the strain CC002/Unc as an exercise-induced paradoxical fat response model in a controlled voluntary exercise study across multiple ages in female mice. We also found sex and genetic differences were consistent with this pattern in a study of forced exercise programs. These results provide a novel model for studies to determine the mechanisms behind paradoxical metabolic responses to exercise, and enable development of more rational personalized exercise recommendations based on factors such as age, sex, and genetic background.

SUBMITTER: McMullan RC

PROVIDER: S-EPMC6009762 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature

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CC002/Unc females are mouse models of exercise-induced paradoxical fat response.

McMullan Rachel C RC Ferris Martin T MT Bell Timothy A TA Menachery Vineet D VD Baric Ralph S RS Hua Kunjie K Pomp Daniel D Smith-Ryan Abbie E AE de Villena Fernando Pardo-Manuel FP

Physiological reports 20180601 12

Exercise results in beneficial health outcomes and protects against a variety of chronic diseases. However, U.S. exercise guidelines recommend identical exercise programs for everyone, despite individual variation in responses to these programs, including paradoxical fat gain. Experimental models of exercise-induced paradoxical outcomes may enable the dissection of underlying physiological mechanisms as well as the evaluation of potential interventions. Whereas several studies have identified in ...[more]

PMID: 29924460

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Project description:UnlabelledThe intestines of obese humans and mice are enriched with Erysipelotrichi, a class within the Firmicutes. Clostridium ramosum, a member of the Erysipelotrichi, is associated with symptoms of the metabolic syndrome in humans. To clarify the possible obesogenic potential of this bacterial species and to unravel the underlying mechanism, we investigated the role of C. ramosum in obesity development in gnotobiotic mice. Mice were associated with a simplified human intestinal (SIHUMI) microbiota of eight bacterial species, including C. ramosum, with the SIHUMI microbiota except C. ramosum (SIHUMIw/oCra), or with C. ramosum only (Cra) and fed a high-fat diet (HFD) or a low-fat diet (LFD). Parameters related to the development of obesity and metabolic diseases were compared. After 4 weeks of HFD feeding, the mouse groups did not differ in energy intake, diet digestibility, gut permeability, and parameters of low-grade inflammation. However, SIHUMI and Cra mice fed the HFD gained significantly more body weight and body fat and displayed higher food efficiency than SIHUMIw/oCra mice fed the HFD. Gene expression of glucose transporter 2 (Glut2) in jejunal mucosa and of fatty acid translocase (CD36) in ileal mucosa was significantly increased in the obese SIHUMI and Cra mice compared with the less obese SIHUMIw/oCra mice. The data demonstrate that the presence of C. ramosum in SIHUMI and Cra mice enhanced diet-induced obesity. Upregulation of small intestinal glucose and fat transporters in these animals may contribute to their increased body fat deposition.ImportanceObesity is a growing health problem worldwide. Changes in the proportions of Bacteroidetes and Firmicutes, the two dominant phyla in the human and the murine intestinal tract, link the intestinal microbiota to obesity. Erysipelotrichi, a class within the Firmicutes, increase in response to high-fat feeding in mice. Clostridium ramosum, a member of the Erysipelotrichi, has been linked to symptoms of the metabolic syndrome. We hypothesized that C. ramosum promotes obesity development and related pathologies. Our experiments in gnotobiotic mice show that C. ramosum promoted diet-induced obesity, probably by enhancing nutrient absorption. Identification of obesogenic bacteria and understanding their mode of action enable the development of novel strategies for the treatment of this epidemic disease. Pharmaceuticals that target obesogenic bacteria or their metabolism could help to prevent and treat obesity and related disorders in the future.

Project description:Early-life overnutrition programs increased risks of metabolic disorders in adulthood. Regular exercise has been widely accepted to be an effective measure to maintain metabolic health. However, the intergenerational effects of maternal exercise and the specific mechanism are largely unclear. Our objective was to investigate whether maternal exercise could alleviate the metabolic disturbances induced by early-life overnutrition in both dams and offspring and to explore the role of gut microbiota in mediating the effects. C57BL/6 female mice were randomly divided into three groups: the control group, which were fed a normal control diet; high-fat group, which received a high-fat diet; and high-fat with exercise intervention group, which was fed a high-fat diet and received a voluntary wheel running training. The diet intervention started from 3 weeks prior to mating and lasted throughout pregnancy and lactation. The exercise intervention was only prior to and during pregnancy. The male offspring got free access to normal chow diet from weaning to 24 weeks of age. Glucose tolerance test and biochemical parameters were detected in dams at weaning and offspring at 8 and 24 weeks of age. Their cecal contents were collected for the 16 s rDNA amplicon sequencing. The results showed that maternal high-fat diet resulted in significant glucose intolerance, insulin resistance, and lipid profiles disorders in both dams and offspring. Maternal exercise markedly improved insulin sensitivity in dams and metabolic disorders in offspring from young into adulthood. The decrease in unfavorable bacteria and the persistent enrichment of short-chain fatty acids-producers from mothers to adult offspring, particularly the genus Odoribacter, were all associated with the improvement of metabolism by maternal exercise. Overall, maternal exercise could significantly mitigate the detrimental effects of a maternal high-fat diet on metabolism in both dams and male offspring. The continuous alterations in gut microbiota might be a critical factor in deciphering the metabolic benefits of maternal exercise, which provides some novel evidence and targets for combating metabolic diseases.

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CC002/Unc females are mouse models of exercise-induced paradoxical fat response.

Publications

CC002/Unc females are mouse models of exercise-induced paradoxical fat response.

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