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Publication
Adipocyte P2Y14 receptors play a key role in regulating whole-body glucose and
lipid homeostasis.
Authors Jain S, Pydi SP, Jung YH, Scortichini M, Kesner EL, Karcz TP, Cook DN, Gavrilova
O, Wess J, Jacobson KA
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal JCI insight
Year 2021
Date Published 5/1/2021
Volume : Pages 6 : Not Specified
PubMed Reference 34027896
Abstract Obesity is the major driver of the worldwide epidemic in type 2 diabetes (T2D).
In the obese state, chronically elevated plasma free fatty acid levels
contribute to peripheral insulin resistance, which can ultimately lead to the
development of T2D. For this reason, drugs that are able to regulate lipolytic
processes in adipocytes are predicted to have considerable therapeutic
potential. Gi-coupled P2Y14 receptor (P2Y14R; endogenous agonist, UDP-glucose)
is abundantly expressed in both mouse and human adipocytes. Because activated
Gi-type G proteins exert an antilipolytic effect, we explored the potential
physiological relevance of adipocyte P2Y14Rs in regulating lipid and glucose
homeostasis. Metabolic studies indicate that the lack of adipocyte P2Y14R
enhanced lipolysis only in the fasting state, decreased body weight, and
improved glucose tolerance and insulin sensitivity. Mechanistic studies
suggested that adipocyte P2Y14R inhibits lipolysis by reducing lipolytic enzyme
activity, including ATGL and HSL. In agreement with these findings, agonist
treatment of control mice with a P2Y14R agonist decreased lipolysis, an effect
that was sensitive to inhibition by a P2Y14R antagonist. In conclusion, we
demonstrate that adipose P2Y14Rs were critical regulators of whole-body glucose
and lipid homeostasis, suggesting that P2Y14R antagonists might be beneficial
for the therapy of obesity and T2D.




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