Inverse agonism of the FFA4 free fatty acid receptor controls both adipogenesis and mature adipocyte function

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Alshammari, W S and Duncan, E M and Vita, L and Kenawy, M and Dibnah, B and Wabitsch, M and Gould, G W and Hudson, B D (2025) Inverse agonism of the FFA4 free fatty acid receptor controls both adipogenesis and mature adipocyte function. Cellular Signalling, 131. 111714. ISSN 1873-3913 (https://doi.org/10.1016/j.cellsig.2025.111714)

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Abstract

Adipocyte disfunction is an important component of many metabolic disorders and there is a need for pharmacological approaches that can restore normal adipocyte function. The FFA4 receptor is a G protein coupled receptor (GPCR), activated by long chain free fatty acids (FFAs), that controls adipocyte function. Importantly, adipocytes produce FFAs, which may directly activate FFA4 and there is a need to better understand how FFAs produced by adipocytes interact with FFA4 signalling. In this study we have employed human and mouse adipocyte cell models to determine how pharmacological agonism or antagonism of FFA4 affects adipogenesis, lipolysis and glucose uptake. We show that a commonly used FFA4 antagonist, AH7614, is an inverse agonist and that treating adipocytes with this compound suppressed adipogenesis, inhibits glucose uptake and enhances isoprenaline stimulated lipolysis. In contrast, treatment with a synthetic FFA4 agonist, TUG-891, has only modest effects on adipogenesis and lipolysis, while showing no effect on glucose uptake. To explore the mechanism for why AH7614 but not TUG-891 affects adipocyte function, we demonstrate that during adipogenic differentiation sufficient FFAs are released into the culture medium to activate FFA4, suggesting AH7614 inhibits an autocrine feedback loop to suppress adipogenesis. In contrast, during lipolysis experiments, insufficient FFAs were released to activate the receptor, suggesting that AH7614 must enhance lipolysis by either inhibiting ligand independent FFA4 signalling, or FFA signalling that does not require the FFAs to be released from the cell. This study will help establish how FFA4 targeting therapeutics could be used to treat adipocyte dysfunction. [Abstract copyright: Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.]

ORCID iDs

Alshammari, W S, Duncan, E M, Vita, L, Kenawy, M, Dibnah, B, Wabitsch, M, Gould, G W ORCID logoORCID: https://orcid.org/0000-0001-6571-2875 and Hudson, B D;
CORE (COnnecting REpositories)