β-Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue
Emmanuel Somm, … , Gilbert Greub, Nelly Pitteloud
Emmanuel Somm, … , Gilbert Greub, Nelly Pitteloud
Published April 20, 2017
Citation Information: JCI Insight. 2017;2(8):e91809. https://doi.org/10.1172/jci.insight.91809.
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Research Article Endocrinology Metabolism

β-Klotho deficiency protects against obesity through a crosstalk between liver, microbiota, and brown adipose tissue

Abstract

β-Klotho (encoded by Klb) is the obligate coreceptor mediating FGF21 and FGF15/19 signaling. Klb–/– mice are refractory to beneficial action of pharmacological FGF21 treatment including stimulation of glucose utilization and thermogenesis. Here, we investigated the energy homeostasis in Klb–/– mice on high-fat diet in order to better understand the consequences of abrogating both endogenous FGF15/19 and FGF21 signaling during caloric overload. Surprisingly, Klb–/– mice are resistant to diet-induced obesity (DIO) owing to enhanced energy expenditure and BAT activity. Klb–/– mice exhibited not only an increase but also a shift in bile acid (BA) composition featured by activation of the classical (neutral) BA synthesis pathway at the expense of the alternative (acidic) pathway. High hepatic production of cholic acid (CA) results in a large excess of microbiota-derived deoxycholic acid (DCA). DCA is specifically responsible for activating the TGR5 receptor that stimulates BAT thermogenic activity. In fact, combined gene deletion of Klb and Tgr5 or antibiotic treatment abrogating bacterial conversion of CA into DCA both abolish DIO resistance in Klb–/– mice. These results suggested that DIO resistance in Klb–/– mice is caused by high levels of DCA, signaling through the TGR5 receptor. These data also demonstrated that gut microbiota can regulate host thermogenesis via conversion of primary into secondary BA. Pharmacologic or nutritional approaches to selectively modulate BA composition may be a promising target for treating metabolic disorders.

Authors

Emmanuel Somm, Hugues Henry, Stephen J. Bruce, Sébastien Aeby, Marta Rosikiewicz, Gerasimos P. Sykiotis, Mohammed Asrih, François R. Jornayvaz, Pierre Damien Denechaud, Urs Albrecht, Moosa Mohammadi, Andrew Dwyer, James S. Acierno Jr., Kristina Schoonjans, Lluis Fajas, Gilbert Greub, Nelly Pitteloud

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Figure 6

Modification of gut microbiota composition in Klb–/– mice on chow and high-fat diet (HFD).

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Modification of gut microbiota composition in Klb–/– mice on chow and hi...
(A) Shannon species diversity index. (B) Principal component analysis (PCA). (C) Dendrogram of UniFrac distances illustrating the phylogenetic clustering. (D) Proportions of gut bacteria at the phylum level. (E) Relative abundance of gut bacteria at the phylum level. (F) Relative abundance of gut bacteria at the family level. (G) Relative abundance of gut bacteria at the genus level. In A and E, results are expressed as the mean ± SEM. Chow diet: n = 11 Klb–/– and n = 11 WT male mice. HFD: n = 6 Klb–/– and n = 10 WT male mice. *P < 0.05 versus diet-matched WT (genotype effect); #P < 0.05 for HFD versus chow group for the same genotype (diet effect) determined by ANOVA. In F and G, each column represents the microbiota of 1 animal. B, Bacteroidetes; F, Firmicutes; P, Proteobacteria; D, Deferribacteres; V, Verrucomicrobia.