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

• DOI: 10.1172/jci.insight.91809
• Publication Date: 2017-04-19T15:00:56Z
• Authors: Emmanuel Somm; Hugues Henry; Stephen J. Bruce; Sébastien Aeby; Marta Rosikiewicz; Gerasimos P. Syki...; Mohammed Asrih; François R. Jorna...; Pierre Damien Den...; Urs Albrecht; Moosa Mohammadi; Andrew Dwyer; James S. Acierno; Kristina Schoonjans; Lluis Fajas; Gilbert Greub; Nelly Pitteloud
• Keywords: Deoxycholic acid; FGF21; Energy homeostasis

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