Autocrine negative feed-back regulation of lipolysis through sensing of NEFAs by FFAR4/GPR120 in WAT

Anna Sofie Husted, Jeppe H. Ekberg, Emma Tripp, Tinne A.D. Nissen, ... Thue W. Schwartz

Graphical Abstract/Figure 5. Simplified schematic overview of control of lipolysis by GPCRs with focus on FFAR4 in the context of the other putative autocrine feed-back mechanisms. To the left is indicated the autocrine NEFA and FFAR4 and Gi-mediated autocrine negative feed-back loop on lipolysis characterized in the present study including the pharmacological FFAR4 tool compounds used. In green are indicated the classical catecholamine, β1-receptor, Gs, and adenylate cyclase (AC) mediated stimulatory control of lipolysis. To the right are indicated six different Gi-coupled metabolite sensing GPCRs, which all under different physiological circumstances presumably all act as autocrine regulators of lipolysis and other adipocyte functions: The adenosine A1 receptor, which is responsible for the original, classical autocrine effects of adenosine [52]; the lactate receptor HCAR1/GPR81, which is responsible for the insulin, glucose-mediated inhibition of lipolysis [47]; the HCAR2/GPR109A receptor for circulating and possibly also locally produced β-hydroxybutyrate and the prototype antilipolytic drug niacin [53]; the HCAR3/GPR109B receptor for β-hydroxyoctanoate [54]; the SUCNR1/GPR91 receptor sensing stress, hypoxia induced succinate excretion [39]; and FFAR2/GPR43 which senses acetate conceivably both through autocrine and paracrine mechanism from certain subtypes of adipocytes [55].Autocrine negative feed-back regulation of lipolysis through sensing of NEFAs by FFAR4/GPR120 in WAT.


Long chain fatty acids (LCFAs) released from adipocytes inhibit lipolysis through an unclear mechanism. We hypothesized that the LCFA receptor, FFAR4 (GPR120), which is highly expressed in adipocytes could be involved in this feed-back regulation.

Methods and Results

LC-MS analysis of conditioned media from isoproterenol-stimulated primary cultures of murine and human adipocytes demonstrated that most of the released non-esterified free fatty acids (NEFAs) are known agonists for FFAR4. In agreement with this, conditioned medium from isoproterenol-treated adipocytes stimulated signaling strongly in FFAR4 transfected COS-7 cells as opposed to non-transfected control cells. In transfected 3T3-L1 cells, FFAR4 agonism stimulated Gi- and Go-mini G protein binding more strongly than Gq – effects which were blocked by the selective FFAR4 antagonist AH7614. In primary cultures of murine white adipocytes, the synthetic, selective FFAR4 agonist CpdA inhibited isoproterenol-induced intracellular cAMP accumulation in a manner similar to the antilipolytic control agent nicotinic acid acting through another receptor, HCAR2. In vivo, oral gavage with the synthetic, specific FFAR4 agonist CpdB decreased the level of circulating NEFAs in fasting lean mice to a similar degree as nicotinic acid. In agreement with the identified anti-lipolytic effect of FFAR4, plasma NEFAs and glycerol were increased in FFAR4 deficient mice as compared to littermate controls despite having elevated insulin levels; and, cAMP accumulation in primary adipocyte cultures was augmented by treatment with the FFAR4 antagonist conceivably by blocking the stimulatory tone of endogenous NEFAs on FFAR4.


In white adipocytes FFAR4 functions as a NEFA-activated, autocrine, negative feed-back regulator of lipolysis by decreasing cAMP conceivably though Gi-mediated signaling.