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

ABSTRACT: ?-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.

SUBMITTER: Somm E

PROVIDER: S-EPMC5396514 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Somm Emmanuel E Henry Hugues H Bruce Stephen J SJ Aeby Sébastien S Rosikiewicz Marta M Sykiotis Gerasimos P GP Asrih Mohammed M Jornayvaz François R FR Denechaud Pierre Damien PD Albrecht Urs U Mohammadi Moosa M Dwyer Andrew A Acierno James S JS Schoonjans Kristina K Fajas Lluis L Greub Gilbert G Pitteloud Nelly N

JCI insight 20170420 8

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-indu ...[more]

PMID: 28422755

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Project description:The inflammasome has been recently implicated in obesity-associated dys-metabolism. However, of its products, the specific role of IL-1? was clinically demonstrated to mediate only the pancreatic beta-cell demise, and in mice mainly the intra-hepatic manifestations of obesity. Yet, it remains largely unknown if IL-1?, a cytokine believed to mainly function locally, could regulate dysfunctional inter-organ crosstalk in obesity. Here we show that High-fat-fed (HFF) mice exhibited a preferential increase of IL-1? in portal compared to systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1?KO donors resulted in lower pyruvate-glucose flux compared to mice receiving wild-type (WT) transplant. These results raised a putative endocrine function for visceral fat-derived IL-1? in regulating hepatic gluconeogenic flux. IL-1?KO mice on HFF exhibited only a minor or no increase in adipose expression of pro-inflammatory genes (including macrophage M1 markers), Mac2-positive crown-like structures and CD11b-F4/80-double-positive macrophages, all of which were markedly increased in WT-HFF mice. Further consistent with autocrine/paracrine functions of IL-1? within adipose tissue, adipose tissue macrophage lipid content was increased in WT-HFF mice, but significantly less in IL-1?KO mice. Ex-vivo, adipose explants co-cultured with primary hepatocytes from WT or IL-1-receptor (IL-1RI)-KO mice suggested only a minor direct effect of adipose-derived IL-1? on hepatocyte insulin resistance. Importantly, although IL-1?KOs gained weight similarly to WT-HFF, they had larger fat depots with similar degree of adipocyte hypertrophy. Furthermore, adipogenesis genes and markers (pparg, cepba, fabp4, glut4) that were decreased by HFF in WT, were paradoxically elevated in IL-1?KO-HFF mice. These local alterations in adipose tissue inflammation and expansion correlated with a lower liver size, less hepatic steatosis, and preserved insulin sensitivity. Collectively, we demonstrate that by promoting adipose inflammation and limiting fat tissue expandability, IL-1? supports ectopic fat accumulation in hepatocytes and adipose-tissue macrophages, contributing to impaired fat-liver crosstalk in nutritional obesity.

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

Publications

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

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