RESUMEN
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.
Asunto(s)
Obesidad/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Adipocitos/metabolismo , Adipocitos/patología , Adipogénesis , Tejido Adiposo/metabolismo , Tejido Adiposo/patología , Animales , Señalización del Calcio , Diferenciación Celular , Análisis Mutacional de ADN , Dieta Alta en Grasa , Metabolismo Energético , Europa (Continente)/etnología , Exones/genética , Hígado Graso/complicaciones , Hígado Graso/genética , Regulación de la Expresión Génica , Péptido 1 Similar al Glucagón/metabolismo , Glucosa/metabolismo , Intolerancia a la Glucosa/complicaciones , Humanos , Insulina/metabolismo , Resistencia a la Insulina , Lipogénesis , Hígado/metabolismo , Macrófagos/metabolismo , Ratones , Mutación/genética , Obesidad/complicaciones , Obesidad/genética , Obesidad/patología , Receptores Acoplados a Proteínas G/deficiencia , Receptores Acoplados a Proteínas G/genética , Transducción de Señal/genética , Población Blanca/genéticaRESUMEN
It has recently been suggested that the low-frequency c.136-14_136-13insC variant in high-mobility group A1 (HMGA1) may strongly contribute to insulin resistance and type 2 diabetes risk. In our study, we attempted to confirm that HMGA1 is a novel type 2 diabetes locus in French Caucasians. The gene was sequenced in 368 type 2 diabetic case subjects with a family history of type 2 diabetes and 372 normoglycemic control subjects without a family history of type 2 diabetes. None of the 41 genetic variations identified were associated with type 2 diabetes. The lack of association between the c.136-14_136-13insC variant and type 2 diabetes was confirmed in an independent French group of 4,538 case subjects and 4,015 control subjects and in a large meta-analysis of 16,605 case subjects and 46,179 control subjects. Finally, this variant had no effects on metabolic traits and was not involved in variations of HMGA1 and insulin receptor (INSR) expressions. The c.136-14_136-13insC variant was not associated with type 2 diabetes in individuals of European descent. Our study emphasizes the need to analyze a large number of subjects to reliably assess the association of low-frequency variants with the disease.