Dysfunction of lipid sensor GPR120 leads to obesity in both mouse and human

Abstract

Free fatty acids provide an important energy source as nutrients, and act as signalling molecules in various cellular processes. Several G-protein-coupled receptors have been identified as free-fatty-acid receptors important in physiology as well as in several diseases. GPR120 (also known as O3FAR1) functions as a receptor for unsaturated long-chain free fatty acids and has a critical role in various physiological homeostasis mechanisms such as adipogenesis, regulation of appetite and food preference. Here we show that GPR120-deficient mice fed a high-fat diet develop obesity, glucose intolerance and fatty liver with decreased adipocyte differentiation and lipogenesis and enhanced hepatic lipogenesis. Insulin resistance in such mice is associated with reduced insulin signalling and enhanced inflammation in adipose tissue. In human, we show that GPR120 expression in adipose tissue is significantly higher in obese individuals than in lean controls. GPR120 exon sequencing in obese subjects reveals a deleterious non-synonymous mutation (p.R270H) that inhibits GPR120 signalling activity. Furthermore, the p.R270H variant increases the risk of obesity in European populations. Overall, this study demonstrates that the lipid sensor GPR120 has a key role in sensing dietary fat and, therefore, in the control of energy balance in both humans and rodents.

Is Palmitoleic Acid a Plausible Nonpharmacological Strategy to Prevent or Control Chronic Metabolic and Inflammatory Disorders?

“…[3] On other hand, following the lower production of palmitoleic acid, animals with GPR-120 dysfunction showed a downregulation of SCD-1, SREBP, PPARγ in adipose tissue while an upregulation of SCD-1 and high ectopic accumulation of triglycerides in their liver occurred when they were fed a high-fat diet. [74] Administration of palmitoleic acid to genetic type-2 diabetic mice reduced lipid accumulation and lipogenic gene expression (SREBP-1, FAS, and SCD-1) in the liver [6] (Table 5). However, studies performed with wild-type animals or PPARα knockout mice were unable to show beneficial effects of palmitoleic acid on the degree of steatosis.…”

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

“…This result was fully consistent with recent publication showing an association of an increase in GPR120 expression with human obesity. 9 G-protein-coupled 40 (GPR40), which is predominantly expressed in pancreatic b-cells 10 shares the same ligands with GPR120. Thus, we also examined GPR40 expression in CRC tissues using IHC staining, and RT-PCR.…”

“…However, one of nonsynonymous GPR120 variants lost the ability to transduce the signal of long-chain free fatty acids. 9 This study prompted us to detect whether overexpressed GPR120 in CRC cells could respond to ligand stimulation, which was the basis of its biology. Overexpressed GPR120 in these CRC cells was functional and signaled via a Gaq/11-coupled pathway, similar to GPR120-expressing RAW 264.7 cells and mature adipocytes.…”

“…6,7 More recently, GPR120 has been shown to exert effects in regulating inflammation, mediating insulin sensitization and reducing obesity. 8,9 However, there is no report about the expression of GPR120 in tumors, and the role of GPR120 in tumor development is unknown, even though GPR120 is abundantly expressed in intestine.…”

Les récepteurs membranaires des acides gras de la cellule β

“…Oh et al [29] ont montré, chez des souris invalidées pour le gène gpr120, que ce récepteur est responsable des effets antiinflammatoires et insulinosensibilisants des acides gras oméga-3, DHA et EPA, in vivo. Ces observations chez la souris sont corroborées par la découverte récente d'une mutation du gène GPR120 associée à une augmentation de 60 % du risque d'obésité chez l'homme [30]. L'expression de GPR120 dans les cellules β a été détectée par RT-PCR (reverse transcriptase-polymerase chain reaction) [31], mais son rôle physiologique dans ce type cellulaire est mal connu.…”