Adipocyte P2Y14 receptors play a key role in regulating whole-body glucose and lipid homeostasis
Shanu Jain, … , Jürgen Wess, Kenneth A. Jacobson
Shanu Jain, … , Jürgen Wess, Kenneth A. Jacobson
Published May 24, 2021
Citation Information: JCI Insight. 2021;6(10):e146577. https://doi.org/10.1172/jci.insight.146577.
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Research Article Metabolism

Adipocyte P2Y14 receptors play a key role in regulating whole-body glucose and lipid homeostasis

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.

Authors

Shanu Jain, Sai P. Pydi, Young-Hwan Jung, Mirko Scortichini, Efrat L. Kesner, Tadeusz P. Karcz, Donald N. Cook, Oksana Gavrilova, Jürgen Wess, Kenneth A. Jacobson

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Figure 1

P2Y14R mRNA in human subcutaneous fat; activation of P2Y14R inhibits lipolysis in vitro.

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P2Y14R mRNA in human subcutaneous fat; activation of P2Y14R inhibits lip...
(A) Relative P2Y14R mRNA expression in subcutaneous fat from lean and obese humans (n = 3–4/group). (B) P2Y14 R mRNA and BMI correlation in lean and obese humans (n = 8). (C) P2Y14 R mRNA and fat mass (%) correlation in lean and obese human individuals (n = 8). (D) Relative expression of P2Y14 R mRNA in subcutaneous (iWAT), visceral (eWAT), and brown (BAT) mouse adipose tissues (n = 3–4/group). (E) P2Y14 R mRNA levels in iWAT, eWAT (mature adipocytes), and BAT from C57BL/6 control mice (n = 3 or 4/group) on RC or HFD. (F) Relative cAMP response in differentiated mature adipocytes (iWAT) from control mice, treated with CL-316243 (10 nM) (β3-adrenergic receptor-selective agonist) or MRS2905 with CL-316243 (10 nM), as indicated (n = 4/group). (G) Glycerol release in differentiated mature adipocytes (iWAT) from control mice stimulated with MRS2905 (2 nM) for 30 min. Cells were then treated with CL-316243 (10 nM), as indicated. (n = 3/group). (H) Glycerol release in differentiated mature adipocytes (iWAT) treated with vehicle or PPTN (200 nM) for 30 min, followed by insulin (10 nM) and/or CL-316,243 (10 nM) (n = 3/group). (I) Western blot analysis of p-ATGL/T-ATGL and p-HSL/T-HSL protein expression in differentiated mature adipocytes (iWAT, control mice) and treated with P2Y14R agonist (MRS2905, 2 nM) for 30 min, followed by CL-316243 (10 nM) for 30 min, as indicated. Representative blots are shown (n = 3 or 4 independent experiments). (J) Quantification of immunoblotting data shown in I. The expression of 18s rRNA was used to normalize qRT-PCR data. All data are expressed as mean ± SEM. *P < 0.05, **P < 0.01 (A–E and J: 2-tailed Student’s t test; F–H: 1-way ANOVA followed by Bonferroni’s post hoc test). All preadipocytes were isolated from RC-fed mice and differentiated to mature adipocytes for experiments. P2Y, purinergic; RC, regular chow; HFD, high-fat diet; ATGL, adipose triglyceride lipase; HSL, hormone-sensitive lipase.