Lack of Adipocyte Purinergic P2Y₆Receptor Greatly Improves Whole Body Glucose Homeostasis

Abstract

Uridine diphosphate (UDP)-activated purinergic receptor P2Y 6 (P2Y 6 R) plays a crucial role in controlling energy balance through central mechanisms. However, P2Y 6 R's roles in peripheral tissues regulating energy and glucose homeostasis remain unexplored. Here, we report the surprising novel finding that adipocyte-specific deletion of P2Y 6 R protects mice from dietinduced obesity, improving glucose tolerance and insulin sensitivity with reduced systemic inflammation. These changes were associated with reduced JNK signaling, and enhanced expression and activity of PPARα affecting downstream PGC1α levels leading to beiging of white fat. In contrast, P2Y 6 R deletion in skeletal muscle reduced glucose uptake resulting in impaired glucose homeostasis. Interestingly, whole body P2Y 6 R KO mice showed metabolic improvements similar to those observed with mice lacking P2Y 6 R only in adipocytes. Our findings provide compelling evidence that P2Y 6 R antagonists may prove useful for the treatment of obesity and type 2 diabetes.

Metabolic roles of G protein‐coupled receptor signaling in obesity and type 2 diabetes

“…In C2C12 cells, activation of P2Y 6 R purinergic receptors (P2Y 6 Rs) increased GLUT4 translocation to the cell membrane by enhancing AMPK signaling, thereby increasing glucose uptake [151]. Consistent with this observation, ablation of P2Y 6 R specifically in SKM impaired whole-body glucose homeostasis and insulin sensitivity [34]. Lack of P2Y 6 R signaling reduced insulin-mediated glucose uptake in SKM (Fig.…”

“…Lack of P2Y 6 R signaling reduced insulin‐mediated glucose uptake in SKM (Fig. 3; Table 1) [34]. A recent in vivo study examined mice that expressed a Gq‐linked designer GPCR (Gq DREADD) selectively in SKM [35].…”

“…showed that lack of P2Y 6 Rs in adipocytes protects mice from diet‐induced obesity and reduces inflammation and JNK activity in adipose tissues, suggesting that P2Y 6 R may be a potential target to treat adiposity and systemic inflammation in obese patients (Fig. 4A; Table 1) [265].…”

“…Originally, beta-arrestins were identified as regulators of GPCR internalization and desensitization [22]; however, more recent studies have shown that beta-arrestins can also act as signaling molecules on their own, mediating G protein-independent signaling [23][24][25][26][27][28][29][30]. GPCRs modulate a very large number of metabolic functions including glucose production, glucose uptake, insulin action, insulin secretion, and differentiation and expansion of various cell types [5,[31][32][33][34][35][36][37]. Thus, it is not surprising that GPCRs have emerged as prime drug targets for the treatment of metabolic diseases such as obesity and T2D.…”

Purinergic Signaling in Liver Pathophysiology

“…Recent studies have demonstrated the role of P2Y receptors in regulating obesity and its impact on liver steatosis and inflammation. Mice lacking P2Y 6 R selectively in adipocytes were protected from diet-induced obesity (without a significant change in food intake) and systemic inflammation ( 71 ). Reduced obesity in adipocyte-P2Y 6 R KO resulted in lower liver weight and hepatic steatosis ( 71 ).…”