Genetic disruption of uncoupling protein 1 in mice renders brown adipose tissue a significant source of FGF21 secretion

Abstract

ObjectiveCirculating fibroblast growth factor 21 (FGF21) is an important auto- and endocrine player with beneficial metabolic effects on obesity and diabetes. In humans, thermogenic brown adipose tissue (BAT) was recently suggested as a source of FGF21 secretion during cold exposure. Here, we aim to clarify the role of UCP1 and ambient temperature in the regulation of FGF21 in mice.MethodsWildtype (WT) and UCP1-knockout (UCP1 KO) mice, the latter being devoid of BAT-derived non-shivering thermogenesis, were exposed to different housing temperatures. Plasma metabolites and FGF21 levels were determined, gene expression was analyzed by qPCR, and tissue histology was performed with adipose tissue.ResultsAt thermoneutrality, FGF21 gene expression and serum levels were not different between WT and UCP1 KO mice. Cold exposure led to highly increased FGF21 serum levels in UCP1 KO mice, which were reflected in increased FGF21 gene expression in adipose tissues but not in liver and skeletal muscle. Ex vivo secretion assays revealed FGF21 release only from BAT, progressively increasing with decreasing ambient temperatures. In association with increased FGF21 serum levels in the UCP1 KO mouse, typical FGF21-related serum metabolites and inguinal white adipose tissue morphology and thermogenic gene expression were altered.ConclusionsHere we show that the genetic ablation of UCP1 increases FGF21 gene expression in adipose tissue. The removal of adaptive nonshivering thermogenesis renders BAT a significant source of endogenous FGF21 under thermal stress. Thus, the thermogenic competence of BAT is not a requirement for FGF21 secretion. Notably, high endogenous FGF21 levels in UCP1-deficient models and subjects may confound pharmacological FGF21 treatments.

Brown adipose tissue transplantation ameliorates polycystic ovary syndrome

“…After adiponectin treatment, decreased BAT activity, metabolic abnormalities, acyclicity, and abnormal hormonal levels were surprisingly normalized up to normal levels in the PCOS rat. Based on recent publications, BAT also secretes a considerable number of adipokines, such as adiponectin, FGF21, NGF, NRG4, VEGF, and BMPs (16,35). We have observed that there was no significant difference of FGF21 or NGF levels between groups (Table S6).…”

Fibroblast growth factor-21, energy balance and obesity

“…Despite these discrepancies, these results indicate that FGF21 may promote energy expenditure through mechanisms other than the induction of UCP1-mediated uncoupling respiration in brown or beige/brite adipocytes. In fact, UCP1-null mice show a dramatic increase in FGF21 levels and FGF21 expression in BAT and WAT (Keipert et al, 2015;Samms et al, 2015), suggestive of homeostatic compensatory mechanisms for promotion of energy expenditure when the UCP1-mediated mechanisms are blunted.…”

Modulation of energy balance by fibroblast growth factor 21

“…However, when UCP1 is absent in UCP1-null mice, FGF21 decrease appetite and food intake resulting in weight loss as well [61,116]. Interestingly, UCP1-null mice showed impressive increment in FGF21 levels with very high expression in BAT and WAT [61,117]. Therefore, FGF21 is an important compensatory mechanism when UCP1 mechanism is diminished, and anti-obesity effect do not necessarily involve the generation of brown adipocytes in WAT and UCP1 activity in mice [116].…”