The role of the G-protein coupled receptor 120 (GPR120) on the FGF21 system in white and brown adipose tissues

Abstract

Obesity prevalence has tripled in the last fifty years. For this reason, it is considered the pandemic of the century. It is characterized by the accumulation of metabolic abnormalities triggered by an increase in the size of fat depots in the body. Hence, new therapies to pursue an amelioration of metabolic abnormalities and adipose tissue dysfunction caused by this energy imbalance are being explored. The tissue responsible for the storage of fat is adipose tissue and it was considered just as an energy reservoir until recently. Currently, it is known to be actively involved in energy homeostasis at the same time that it fulfills endocrine functions. Adipose tissue is divided into two main types, white adipose tissue (WAT) and brown adipose tissue (BAT). While energy storage is the main role of WAT, BAT is able to dissipate energy in the form of heat leading to an increased energy expenditure. Surprisingly, it has been reported that WAT has the ability to recruit cells of the brown phenotype and thus increase its energy expenditure in a process denominated as browning. BAT activity and WAT browning are important components of energy expenditure and therefore potential therapeutic targets for the treatment of obesity and its comorbidities. In this work, we show that GPR120 activation, a membrane receptor for polyunsaturated fatty acids (PUFAs), promotes BAT thermogenic activity and WAT browning. The tissue that reported the highest levels of GPR120 expression is BAT, followed by colon and WAT different deposits. In addition, it was discovered that thermal stress (cold exposure) causes an induction in the expression of GPR120 in adipose depots. Likewise, the activation of GPR120 induces an increase in oxygen consumption. Conversely, mice deficient of GPR120 show decreased temperature and UCP1 expression in neonatal BAT and decreased browning after cold exposure in adult WAT. The administration of natural or synthetic agonists of GPR120, such as omega-3 PUFAs or GW9508, induced brown and beige adipocyte differentiation as well as their thermogenic activation and glucose oxidation. This activation by n-3 PUFAs was dependent of GPR120 expression. In addition to these findings, it was revealed that the activation of GPR120 induces the expression and release of fibroblast growth factor-21 (FGF21) by BAT and WAT at the same time that it increases plasma FGF21 levels. FGF21 is a hormonal factor able to induce thermogenic activation of BAT and browning of WAT, both associated with an improvement in metabolic conditions. In the absence of GPR120, the levels of FGF21 under cold stress conditions are decreased. Furthermore, n-3 PUFAs and synthetic agonists do not induce the expression and release of FGF21 in animals and cells deficient of GPR120. Regarding the effects on the activation of BAT, browning of WAT and the increase in glucose oxidation by the activation of GPR120, these are all compromised in mice or adipocytes lacking FGF21. Therefore, it is concluded that GPR120 activation induces BAT thermogenic activity and WAT browning through a mechanism that involves the induction of FGF21.

La obesidad es pandemia del siglo XXI y se caracteriza por desencadenar anomalías metabólicas debido al exceso de grasa almacenada en el organismo. Ello urge la exploración de nuevas terapias para su tratamiento. El tejido adiposo (TA) ha pasado de considerarse solo un depósito de energía a ser relacionado con el mantenimiento de la homeostasis energética. Se divide en dos tipos, tejido adiposo blanco (TAB) y tejido adiposo marrón (TAM). El primero sirve como almacén de energía y el segundo produce calor debido al desacoplamiento de la cadena respiratoria resultando en un gasto energético incrementado. El TAB tiene la capacidad de reclutar células del fenotipo marrón en un proceso denominado pardeamiento. La actividad del TAM y el pardeamiento del TAB son componentes importantes del gasto energético y blancos terapéuticos para el tratamiento de la obesidad. GPR120 es un receptor de membrana para ácidos grasos poliinsaturados (PUFAs) que demostró promover la activación del TAM y el pardeamiento del TAB. El TAM es el tejido que expresa GPR120 principalmente y el estrés térmico causa una inducción en la expresión de GPR120 en los depósitos adiposos. Conjuntamente, la activación de GPR120 induce la actividad termogénica del TAM y pardeamiento del TAB. Inversamente, los ratones deficientes de GPR120 muestran una activación de la termogénesis disminuida tras la exposición al frío. Además, la activación de GPR120 ha mostrado inducir la diferenciación de adipocitos marrón y beige así como su activación termogénica. Dicha activación conlleva a la inducción en la expresión y liberación del factor de crecimiento fibroblástico-21 (FGF21) por el TA así como un aumento en los niveles en sangre. FGF21 es un factor hormonal capaz de inducir la termogénesis en el TA y de mejorar las condiciones metabólicas. Los animales deficientes de GPR120 muestran niveles de FGF21 disminuidos tras la exposición a frío mientras que la falta de FGF21 comprometió la inducción de la termogénesis tras la activación de GPR120 en ratones y adipocitos. Se concluyó que la activación de GPR120 induce la actividad termogénica de la grasa marrón y el pardeamiento de la grasa blanca a través de la inducción de FGF21.