Bile acids induce uncoupling protein 1-dependent thermogenesis and stimulate energy expenditure at thermoneutrality in mice

Abstract

Zietak M, Kozak LP. Bile acids induce uncoupling protein 1-dependent thermogenesis and stimulate energy expenditure at thermoneutrality in mice. Am J Physiol Endocrinol Metab 310: E346 -E354, 2016. First published December 29, 2015; doi:10.1152/ajpendo.00485.2015.-It has been proposed that diet-induced obesity at thermoneutrality (TN; 29°C) is reduced by a UCP1-dependent thermogenesis; however, it has not been shown how UCP1-dependent thermogenesis can be activated in the absence of sympathetic activity. A recent study provides such a mechanism by showing that dietary bile acids (BAs) suppress obesity in mice fed a high-fat diet (HFD) by a mechanism dependent on type 2 deiodinase (DIO2); however, neither a role for UCP1 nor the influence of sympathetic activity was properly assessed. To test whether the effects of BAs on adiposity are independent of Ucp1 and cold-activated thermogenesis, obesity phenotypes were determined in C57BL6/J. ϩ / ϩ (WT) and C57BL6/J.Ucp1. Ϫ / Ϫ mice (Ucp1-KO) housed at TN and fed a HFD with or without 0.5% (wt/wt) cholic acid (CA) for 9 wk. CA in a HFD reduced adiposity and hepatic lipogenesis and improved glucose tolerance in WT but not in Ucp1-KO mice and was accompanied by increases in food intake and energy expenditure (EE). In iBAT, CA increased Ucp1 mRNA and protein levels 1.5-and twofold, respectively, and increased DIO2 and TGR5 protein levels in WT mice. Despite enhanced Dio2 expression in Ucp1-KO and Ucp1-KO-CA treated mice, this did not enhance the ability of BAs to reduce obesity. By comparing the effects of BAs on WT and Ucp1-KO mice at TN, our study showed that BAs suppress diet-induced obesity by increasing EE through a mechanism dependent on Ucp1 expression, which is likely independent of adrenergic signaling.brown adipose tissue; diet-induced obesity; mitochondrial uncoupling protein 1; bile acids; thermogenesis; type 2 deidodinase IN MICE, A MAJOR MECHANISM for maintaining body temperature in a cold environment involves induction of uncoupling protein 1 (UCP1)-dependent thermogenesis in brown adipose tissue (BAT) (7). The consequence of this increase in energy expenditure (EE) is increased oxidation of lipid stores in the body with overall reductions in adipose tissue fat stores. Most of this enhanced thermogenesis in the cold is mediated by sympathetically activated thermogenesis by BAT (4), (10). It has been reported that dietary bile acids (BAs) suppress the development of diet-induced obesity by a mechanism in which BAs activate the type 2 deiodinase (DIO2) pathway through the G-coupled receptor TGR5 (GPR131 or GpBAR1; a G protein-coupled plasma membrane receptor for BAs) (27). DIO2 was implicated in the mechanism through the use of Dio2-KO (Dio2-knockout) mice, which were resistant to the weight-reducing effects of BAs (27). However, since the expression of Ucp1 in the Dio2-KO mouse is nearly normal, consistent with the observation that the Dio2-KO mice show only a slight sensitivity to cold exposure (8, 9), and the study was conducted at an undefined ambient temp...

Endogenous FGF21-signaling controls paradoxical obesity resistance of UCP1-deficient mice

“…3h) were detected. Recent studies associate the protection against obesity development to the cold stress-microbiome axis, 28 affecting bile acid (BA) composition and energy assimilation [28][29][30] . The reduction of ambient temperature from 30 to 23°C represents cold stress for UCP1 KO mice.…”

Non-adrenergic control of lipolysis and thermogenesis in adipose tissues

“…In both rodents and humans, BAT is targeted by bile acids. In C57BL/6 mice, dietary supplementation with cholic acid increased the thermogenetic capacity of BAT even in a thermoneutral environment and prevented diet-induced obesity (Teodoro et al, 2014;Watanabe et al, 2006;Zietak and Kozak, 2016). Mechanistically, the binding of bile acids to the TGR5 receptor increased the intracellular concentrations of the second messenger cAMP, which activates expression of the gene encoding for type 2 deiodinase (DIO2).…”

Obesity diabetes and the role of bile acids in metabolism

“…The energy expenditure has not been shown to increase after weight reduction due to hypocaloric diet with or without bariatric surgery [45] . Bile acids have, however, been shown in mice to increase energy expenditure by increasing UCP-1 expression, probably independent of adrenergic signalling [46,47] .…”