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P2Y 14 receptor regulates adipocyte lipid mobilization and whole‐body glucose homeostasis
Author(s) -
Jacobson Kenneth,
Jain Shanu,
Pydi Sai,
Jung YoungHwan,
Scortichini Mirko,
Kesner Efrat,
Karcz Tadeusz,
Cook Donald,
Gavrilova Oksana,
Wess Jürgen
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02001
Subject(s) - lipolysis , endocrinology , medicine , adipocyte , glucose homeostasis , insulin resistance , adipose tissue , insulin , homeostasis , agonist , glucose uptake , chemistry , type 2 diabetes , biology , receptor , diabetes mellitus
The incidence and prevalence of obesity and type 2 diabetes (T2D) is rapidly increasing worldwide. Obesity is associated with chronically elevated plasma free fatty acid (FFA) levels, causing peripheral insulin resistance and T2D. Drugs that are able to regulate adipocyte lipolytic processes, improving insulin sensitivity and whole‐body glucose homeostasis, have considerable therapeutic potential. G i ‐coupled P2Y 14 receptor (P2Y 14 R), activated by UDP‐glucose is abundantly expressed in mouse and human adipocytes. P2Y 14 R activation in primary mouse adipocytes decreased cAMP levels and CL‐316,243 (β 3 ‐adrenoceptor agonist) induced lipolysis. To investigate the physiological relevance of adipocyte P2Y 14 Rs in regulating lipid and glucose homeostasis in‐vivo, we generated a mouse model lacking P2Y 14 R specifically in adipocytes. Lack of adipocyte P2Y 14 R increased lipolysis only in the fasting state, resulting in decreased body weight, improved glucose tolerance and insulin sensitivity. Accordingly, high fat diet increased, whereas fasting decreased P2Y 14 R expression in visceral white adipocytes. Mechanistic studies suggested that activation of P2Y 14 R reduced the activity of lipolytic enzymes including ATGL and HSL, thereby inhibiting lipolysis. Supporting these findings, administration of P2Y 14 R agonist in control mice decreased lipolysis. Coadministration of P2Y 14 R antagonist with the P2Y 14 R agonist rescued the decrease in lipolysis. In conclusion, we demonstrate that lack of adipocyte P2Y 14 R decreased diet‐induced obesity by enhancing lipolysis in the fasting state, suggesting that P2Y 14 R antagonists may prove beneficial for the therapy of obesity and T2D.