Understanding the Mechanism of Fibroblast Growth Factor 21 Action in the Paraventricular Nucleus of the Hypothalamus: A Promising Candidate in the Treatment of Obesity and Metabolic Diseases

Abstract

Fibroblast Growth Factor 21 (FGF21), when administered pharmacologically reduces body weight, increases insulin sensitivity and energy expenditure, and induces browning of white adipose tissue (WAT). Research has shown that FGF21 signaling in the brain is required for the induction of these metabolic benefits, with the paraventricular nucleus of the hypothalamus (PVN) as a potential primary site of action. However, the neuronal circuits and precise mechanisms mediating FGF21’s metabolic effects remain incompletely understood. Further, the role of the sympathetic nervous system (SNS) in this process remains unclear. Here, we aimed to address these questions using dietary methionine restriction (MR) as a tool to stimulate endogenous FGF21 production in WT and FGF21 KO mice fed a control or a high‐fat diet. Dietary MR rapidly and persistently increases serum FGF21 concentration by up to 8‐fold (p<0.0001). We found that in WT mice, MR increased energy expenditure and thermogenic markers in iWAT and BAT, an indication of increased SNS output to these tissues in WT, but not FGF21 KO mice. Additionally, we observed increased ERK phosphorylation in the PVN of the WT but not FGF21 KO mice, supporting PVN neurons as a likely target mediating FGF21 actions. To further investigate the role of FGF21 in the PVN, we used whole‐cell patch clamp recordings in retrogradely‐labelled presympathetic PVN neurons projecting to the rostral ventrolateral medulla (RVLM), and measured the effects of the FGF21 analog LY2405319 (500nM) on the firing activity of PVN‐RVLM neurons. Recordings in current‐clamp mode showed that FGF21 either increased (33% of recorded neurons) or decreased (67% of recorded neurons) the firing activity of these neurons suggesting that FGF21 effects may depend on their projecting targets. Recordings in voltage‐clamp mode also showed that FGF21 significantly decreased the degree of activity of GABAergic inhibitory inputs into these neurons. Thus, LY2405319 inhibited the frequency of GABA inhibitory postsynaptic current (IPSC) (42.02% decrease, p< 0.05), suggesting that FGF21 effects on presympathetic neurons in the PVN could be mediated by direct and/or indirect actions, including modulation of local network activity, such as local GABAergic interneurons. Taken together, our data support the hypothesis that FGF21 signals through PVN neurons to increase SNS output to adipose tissue, resulting in increased energy expenditure, reduced body weight, and improved insulin sensitivity.