P2Y2 Receptor Promotes High-Fat Diet-Induced Obesity

Abstract

P2Y 2 , a G protein-coupled receptor (R), is expressed in all organs involved in the development of obesity and insulin resistance. To explore the role of it in diet-induced obesity, we fed male P2Y 2-R whole body knockout (KO) and wild type (WT) mice (B6D2 genetic background) with regular diet (CNT; 10% calories as fat) or high-fat diet (HFD; 60% calories as fat) with free access to food and water for 16 weeks, and euthanized them. Adjusted for body weights (BW), KO mice consumed modestly, but significantly more HFD vs. WT mice, and excreted well-formed feces with no taint of fat or oil. Starting from the 2nd week, HFD-WT mice displayed significantly higher BW with terminal mean difference of 22% vs. HFD-KO mice. Terminal weights of white adipose tissue (WAT) were significantly lower in the HFD-KO vs. HFD-WT mice. The expression of P2Y 2-R mRNA in WAT was increased by 2-fold in HFD-fed WT mice. Serum insulin, leptin and adiponectin levels were significantly elevated in the HFD-WT mice, but not in the HFD-KO mice. When induced in vitro, preadipocytes derived from KO mice fed regular diet did not differentiate and mature as robustly as those from the WT mice, as assessed by cellular expansion and accumulation of lipid droplets. Blockade of P2Y 2-R by AR-C118925 in preadipocytes derived from WT mice prevented differentiation and maturation. Under basal conditions, KO mice had significantly higher serum triglycerides and showed slightly impaired lipid tolerance as compared to the WT mice. HFD-fed KO mice had significantly better glucose tolerance (GTT) as compared to HFD-fed WT mice. Whole body insulin sensitivity and mRNA expression of insulin receptor, IRS-1 and GLUT4 in WAT was significantly higher in HFD-fed KO mice vs. HFD-fed WT mice. On the contrary, the expression of pro-inflammatory molecules MCP-1, CCR2, CD68, and F4/80 were significantly higher in the WAT of HFD-fed WT vs. HFD-fed KO mice. These data suggest that P2Y 2-R plays a significant role in the development of diet-induced obesity by promoting adipogenesis and inflammation, and altering the production of adipokines and lipids and their metabolism in adipose tissue, and thereby facilitates HFD-induced insulin resistance.

P2Y2R Deficiency Ameliorates Hepatic Steatosis by Reducing Lipogenesis and Enhancing Fatty Acid β-Oxidation through AMPK and PGC-1α Induction in High-Fat Diet-Fed Mice

“…Current treatment strategies aim to improve hepatic steatosis and inflammation by reducing insulin resistance and oxidative stress in obesity-induced NAFLD [ 5 ]. P2Y2R is widely expressed in metabolic organs, such as liver, white adipose tissue and skeletal muscle [ 20 , 21 , 22 ]. P2Y2R activation is involved in various hepatic cellular processes of proliferation, apoptosis, inflammation, and fibrosis [ 32 , 33 , 34 ].…”

“…P2Y2R activation is involved in various hepatic cellular processes of proliferation, apoptosis, inflammation, and fibrosis [ 32 , 33 , 34 ]. A recent study has reported that P2Y2R promotes HFD-induced obesity and insulin resistance by stimulating adipogenesis and inflammatory cytokines, and altering adipokine production and lipid metabolism in adipose tissue [ 22 ]. Consistently, P2Y2R deficient mice inhibit excessive immune cell infiltration, reducing adipose tissue inflammation and ameliorating the HFD-induced metabolic phenotype [ 25 ].…”

“…These extracellular nucleotides stimulate the purinergic P2 (P2Y) receptor, which consists of eight subtypes (P2Y1, P2Y2, P2Y4, P2Y6, and P2Y11-14) [ 19 , 20 ]. Particularly, P2Y2R is expressed in the most metabolic organs associated with obesity and insulin resistance including liver, adipose tissues, skeletal muscle, kidney, intestines and pancreas [ 20 , 21 , 22 ]. Activation of P2Y2R mediates several cellular pathways; in regenerating livers, P2Y2R induces hepatocyte proliferation and cell cycle progression through extracellular signal- regulated kinase (ERK) signaling and the downstream transcriptional activation [ 23 ].…”

“…Previously, it has been reported that constitutive P2Y2R activation inhibits basal lipolysis, whereas pharmacological antagonism or knockdown of P2Y2R increases intracellular cAMP levels and enhances basal lipolysis in human adipocytes [ 24 ]. P2Y2R also plays an active role in adipogenesis and expansion of adipose tissue, lipogenesis and inflammation in white adipose tissue, thereby promoting HFD-induced obesity and insulin resistance [ 21 , 22 , 25 ]. Taken together, the role of P2Y2R in the pathogenesis of NAFLD remains unknown despite its strong relationship with obesity-induced dyslipidemia.…”

Identification of Novel Biomarkers for Metabolic Syndrome Based on Machine Learning Algorithms and Integrated Bioinformatics Analysis

“…TSPAN14 (Tetraspanin 14) can interact with ADAM10 (ADAM Metallopeptidase Domain 10) and then regulate leukocyte development and in ammatory immunity function 54 . Previous studies have demonstrated that P2RY2 (Purinergic Receptor P2Y2) contributes to the development of chronic high-fat diet-induced metabolic dysfunction and insulin resistance 55,56 . Besides, Merz et al suggested that P2RY2 is involved in the process of immune cell in ltration in metabolic syndrome 57 .…”