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      Altered Microbiota Contributes to Reduced Diet-Induced Obesity upon Cold Exposure

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          Summary

          Maintenance of body temperature in cold-exposed animals requires induction of thermogenesis and management of fuel. Here, we demonstrated that reducing ambient temperature attenuated diet-induced obesity (DIO), which was associated with increased iBAT thermogenesis and a plasma bile acid profile similar to that of germ-free mice. We observed a marked shift in the microbiome composition at the phylum and family levels within 1 day of acute cold exposure and after 4 weeks at 12°C. Gut microbiota was characterized by increased levels of  Adlercreutzia, Mogibacteriaceae, Ruminococcaceae, and Desulfovibrio and reduced levels of Bacilli, Erysipelotrichaceae, and the genus rc4-4. These genera have been associated with leanness and obesity, respectively. Germ-free mice fed a high-fat diet at room temperature gained less adiposity and improved glucose tolerance when transplanted with caecal microbiota of mice housed at 12°C compared to mice transplanted with microbiota from 29°C. Thus, a microbiota-liver-BAT axis may mediate protection against obesity at reduced temperature.

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          Highlights

          • Gut microbiota is altered during suppression of obesity in a cold environment

          • Cold-adapted microbiota improves host bile acid and energy metabolism

          • Acute effects of cold-adapted microbiota are linked to thermogenesis in iBAT

          • Cold-adapted microbiota may signal through FXR and AMPK

          Abstract

          Zietak et al. show that the gut microbiota contributes to the beneficial effects of cold on adiposity via a mechanism involving the production of conjugated bile acids and AMPK activation. Transfer of gut microbiota from cold-exposed mice reduces diet-induced obesity in germ-free recipient mice.

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          Most cited references13

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          Activated type 2 innate lymphoid cells regulate beige fat biogenesis.

          Type 2 innate lymphoid cells (ILC2s), an innate source of the type 2 cytokines interleukin (IL)-5 and -13, participate in the maintenance of tissue homeostasis. Although type 2 immunity is critically important for mediating metabolic adaptations to environmental cold, the functions of ILC2s in beige or brown fat development are poorly defined. We report here that activation of ILC2s by IL-33 is sufficient to promote the growth of functional beige fat in thermoneutral mice. Mechanistically, ILC2 activation results in the proliferation of bipotential adipocyte precursors (APs) and their subsequent commitment to the beige fat lineage. Loss- and gain-of-function studies reveal that ILC2- and eosinophil-derived type 2 cytokines stimulate signaling via the IL-4Rα in PDGFRα(+) APs to promote beige fat biogenesis. Together, our results highlight a critical role for ILC2s and type 2 cytokines in the regulation of adipocyte precursor numbers and fate, and as a consequence, adipose tissue homeostasis. PAPERCLIP:
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            High-fat diet determines the composition of the murine gut microbiome independently of obesity.

            The composition of the gut microbiome is affected by host phenotype, genotype, immune function, and diet. Here, we used the phenotype of RELMbeta knockout (KO) mice to assess the influence of these factors. Both wild-type and RELMbeta KO mice were lean on a standard chow diet, but, upon switching to a high-fat diet, wild-type mice became obese, whereas RELMbeta KO mice remained comparatively lean. To investigate the influence of diet, genotype, and obesity on microbiome composition, we used deep sequencing to characterize 25,790 16S rDNA sequences from uncultured bacterial communities from both genotypes on both diets. We found large alterations associated with switching to the high-fat diet, including a decrease in Bacteroidetes and an increase in both Firmicutes and Proteobacteria. This was seen for both genotypes (ie, in the presence and absence of obesity), indicating that the high-fat diet itself, and not the obese state, mainly accounted for the observed changes in the gut microbiota. The RELMbeta genotype also modestly influenced microbiome composition independently of diet. Metagenomic analysis of 537,604 sequence reads documented extensive changes in gene content because of a high-fat diet, including an increase in transporters and 2-component sensor responders as well as a general decrease in metabolic genes. Unexpectedly, we found a substantial amount of murine DNA in our samples that increased in proportion on a high-fat diet. These results demonstrate the importance of diet as a determinant of gut microbiome composition and suggest the need to control for dietary variation when evaluating the composition of the human gut microbiome.
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              A role for brown adipose tissue in diet-induced thermogenesis.

              Measurement of energy balance during voluntary overeating in rats unequivocally establishes the quantitative importance of diet-induced thermogenesis in energy balance. Like cold-induced thermogenesis, this form of heat production involves changes in the activity of the sympathetic nervous system and brown adipose tissue which suggest that this tissue may determine metabolic efficiency and resistance to obesity.
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                Author and article information

                Contributors
                Journal
                Cell Metab
                Cell Metab
                Cell Metabolism
                Cell Press
                1550-4131
                1932-7420
                14 June 2016
                14 June 2016
                : 23
                : 6
                : 1216-1223
                Affiliations
                [1 ]Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, 10-748 Olsztyn, Poland
                [2 ]Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, 41345 Gothenburg, Sweden
                [3 ]Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
                Author notes
                []Corresponding author l.kozak@ 123456pan.olsztyn.pl
                [∗∗ ]Corresponding author fredrik.backhed@ 123456wlab.gu.se
                [4]

                Co-senior author

                Article
                S1550-4131(16)30219-4
                10.1016/j.cmet.2016.05.001
                4911343
                27304513
                3af57da2-be60-4b2d-af73-deaee546334f
                © 2016 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                : 20 July 2015
                : 9 February 2016
                : 6 May 2016
                Categories
                Short Article

                Cell biology
                Cell biology

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