Backhed F, Manchester JK, Semenkovich CF, Gordon JI.. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci USA 104: 979-984
Washington University in St. Louis, San Luis, Missouri, United StatesProceedings of the National Academy of Sciences (Impact Factor: 9.67). 02/2007; 104(3):979-84. DOI: 10.1073/pnas.0605374104
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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[Show abstract] [Hide abstract] 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.
- "The lack of standardized methods represents the main limiting factor. These experiments differ not only in diet composition (Backhed et al., 2007 used WD while Fleissner et al., 2010 "
[Show abstract] [Hide abstract] 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.
- "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. "
[Show abstract] [Hide abstract] 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.
- "| 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) "