Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A

Washington University in St. Louis, San Luis, Missouri, United States
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2007; 104(3):979-84. DOI: 10.1073/pnas.0605374104
Source: PubMed

ABSTRACT The trillions of microbes that colonize our adult intestines function collectively as a metabolic organ that communicates with, and complements, our own human metabolic apparatus. Given the worldwide epidemic in obesity, there is interest in how interactions between human and microbial metabolomes may affect our energy balance. Here we report that, in contrast to mice with a gut microbiota, germ-free (GF) animals are protected against the obesity that develops after consuming a Western-style, high-fat, sugar-rich diet. Their persistently lean phenotype is associated with increased skeletal muscle and liver levels of phosphorylated AMP-activated protein kinase (AMPK) and its downstream targets involved in fatty acid oxidation (acetylCoA carboxylase; carnitine-palmitoyltransferase). Moreover, GF knockout mice lacking fasting-induced adipose factor (Fiaf), a circulating lipoprotein lipase inhibitor whose expression is normally selectively suppressed in the gut epithelium by the microbiota, are not protected from diet-induced obesity. Although GF Fiaf-/- animals exhibit similar levels of phosphorylated AMPK as their wild-type littermates in liver and gastrocnemius muscle, they have reduced expression of genes encoding the peroxisomal proliferator-activated receptor coactivator (Pgc-1alpha) and enzymes involved in fatty acid oxidation. Thus, GF animals are protected from diet-induced obesity by two complementary but independent mechanisms that result in increased fatty acid metabolism: (i) elevated levels of Fiaf, which induces Pgc-1alpha; and (ii) increased AMPK activity. Together, these findings support the notion that the gut microbiota can influence both sides of the energy balance equation, and underscore the importance of considering our metabolome in a supraorganismal context.

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    • "Thus, because of the lack of coherent outcomes, each result described above contributes to increasing the subject's complexity . In summary: (i) the C57BL6 GF model from Backhed et al. (2007) highlights the involvement of gut microbiota and Angplt4 in weight gain; (ii) the C3H GF model from Fleissner et al. (2010) completely excluded a role of gut microbiota and Angptl4 in weight control; (iii) the link between CLA and fat storage remains unclear; and (iv) SCFA (butyrate) could even be considered effective in the treatment of obesity. These conflicting findings do not allow us to achieve a clear-cut conclusion. "
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    ABSTRACT: Obesity is a common and multi-factorial condition. During the last years, different research has been done to clarify the complex mechanisms that occur in this disease. The excessive increase of the adipose tissue depots is the first clear signal of an impaired metabolism. Moreover, the endocannabinoid system (eCB), inflammation regulatory factors and weight control – through the diet – are strictly connected with the obesity development. The gut microbiota has been proposed as one suitable candidate to explain the intricacy of this scenario. Nevertheless, the latest findings are characterized by several conflicting theories that do not allow us to define the precise role of the gut microbiota. This review, through a critical analysis of the relevant literature, underlines the possibility of considering the gut microbiota as a “joining link” between obesity and the adipose tissue.
    Journal of Functional Foods 04/2015; 14. DOI:10.1016/j.jff.2015.02.014 · 3.57 Impact Factor
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    • "Particularly, the gut microbiota can control fatty-acid oxidation in the host via suppression of the AMPactivated protein kinases (AMPKs). By contrast, the gut microbiota can also induce fat storage in the host by suppression of fastinginduced adipose factor (Fiaf) (Bäckhed et al., 2007). These results are valuable in understanding the pathology of obesity because they determine the inside mechanisms of how gut microbiota can contribute to energy balance of the host. "
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    ABSTRACT: The microbiota of the human gut is gaining broad attention owing to its association with a wide range of diseases, ranging from metabolic disorders (e.g. obesity and type 2 diabetes) to autoimmune diseases (such as inflammatory bowel disease and type 1 diabetes), cancer and even neurodevelopmental disorders (e.g. autism). Having been increasingly used in biomedical research, mice have become the model of choice for most studies in this emerging field. Mouse models allow perturbations in gut microbiota to be studied in a controlled experimental setup, and thus help in assessing causality of the complex host-microbiota interactions and in developing mechanistic hypotheses. However, pitfalls should be considered when translating gut microbiome research results from mouse models to humans. In this Special Article, we discuss the intrinsic similarities and differences that exist between the two systems, and compare the human and murine core gut microbiota based on a meta-analysis of currently available datasets. Finally, we discuss the external factors that influence the capability of mouse models to recapitulate the gut microbiota shifts associated with human diseases, and investigate which alternative model systems exist for gut microbiota research. © 2015. Published by The Company of Biologists Ltd.
    Disease Models and Mechanisms 01/2015; 8(1):1-16. DOI:10.1242/dmm.017400 · 4.97 Impact Factor
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    • "| Experimental evidence of the effect of antibiotics or disrupted microbiota on host weight Study Strain or species Treatment (dose, timing) Diet Effect on weight Effect on microbiota Bäckhed et al. (2007) 68 C57BL6J mice Germ-free (NA, lifelong) Western Less weight gain than similarly fed conventionalized mice Absent Fleissner et al. (2010) "
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    ABSTRACT: The intestinal microbiota can influence host metabolism. When given early in life, agents that disrupt microbiota composition, and consequently the metabolic activity of the microbiota, can affect the body mass of the host by either promoting weight gain or stunting growth. These effects are consistent with the role of the microbiota during development. In this Perspective, we posit that microbiota disruptions in early life can have long-lasting effects on body weight in adulthood. Furthermore, we examine the dichotomy between antibiotic-induced repression and promotion of growth and review the experimental and epidemiological evidence that supports these phenotypes. Considering the characteristics of the gut microbiota in early life as a distinct dimension of human growth and development, as well as comprehending the susceptibility of the microbiota to perturbation, will allow for increased understanding of human physiology and could lead to development of interventions to stem current epidemic diseases such as obesity, type 1 diabetes mellitus and type 2 diabetes mellitus.
    Nature Reviews Endocrinology 12/2014; 11(3). DOI:10.1038/nrendo.2014.210 · 13.28 Impact Factor
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