Endocrine Abstracts

FGF21 has recently emerged as a major regulator of metabolism and energy utilisation. FGF21 administration confers multiple metabolic benefits on insulin sensitivity, blood glucose, lipid profile and body weight in rodents and primates. FGF21 acts through a receptor complex consisting of FGF receptors (FGFR 1, 2, 3 or 4) and a co-receptor βKlotho (KLB), crucially required for FGF21 signaling. Although FGFRs are widely expressed, KLB is predominantly expressed in adipose tissue, liver, and hypothalamus making these as primary sites of FGF21 action. In obesity, circulating levels of FGF21 are elevated, and the expected beneficial effects of endogenous FGF21 are impaired suggesting an FGF21 resistance state. However, the precise pathways whereby obesity induces FGF21 resistance remain unknown. In this study, we aim to investigate whether central resistin/TLR4 pathways could contribute to FGF21 resistance. To test this hypothesis, we assessed, in C57BL6 mice and Wistar rats, the impact of ICV resistin infusion on the expression of FGF21 and its receptor components in the hypothalamus and key peripheral insulin target tissues. Here we show that ICV resistin significantly decreased hypothalamic FGF21 expression in both mice and rats. Interestingly, the expression of FGFR1, the most abundant receptor in the hypothalamus, and KLB were also markedly reduced. Similar results were obtained in resistin treated SH-SY5Y neuronal cells. In rat peripheral tissue, ICV resistin increases the expression of FGF21 in both liver and WAT, and markedly reduced WAT expression of FGFR1 and KLB. Importantly, the knockdown of TLR-4 in SH-SY5Y cells almost completely abolished resistin-dependent down regulation of FGFR1 and KLB. Collectively, these findings indicates that central resistin, by a way of TLR4, down-regulates FGF21, FGFR1 and KLB in the hypothalamus and promotes peripheral FGF21 resistance as mirrored by the overexpression of FGF21 in the liver and WAT and the down-regulation of FGFR1 in the muscle and WAT.

Disclosure: This work was supported by funds from University Paris Sud and CNRS (centre national de la recherche scientifique).