Adipocyte Gq signaling is a regulator of glucose and lipid homeostasis in mice.

Takefumi Kimura, Sai P Pydi, Lei Wang, Dhanush Haspula, Yinghong Cui, Huiyan Lu, Gabriele M König, Evi Kostenis, Gregory R Steinberg, Oksana Gavrilova, Jürgen Wess

Nature communications 2022 Mar 29

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Obesity is the major driver of the global epidemic in type 2 diabetes (T2D). In individuals with obesity, impaired insulin action leads to increased lipolysis in adipocytes, resulting in elevated plasma free fatty acid (FFA) levels that promote peripheral insulin resistance, a hallmark of T2D. Here we show, by using a combined genetic/biochemical/pharmacologic approach, that increased adipocyte lipolysis can be prevented by selective activation of adipocyte Gq signaling in vitro and in vivo (in mice). Activation of this pathway by a Gq-coupled designer receptor or by an agonist acting on an endogenous adipocyte Gq-coupled receptor (CysLT2 receptor) greatly improved glucose and lipid homeostasis in obese mice or in mice with adipocyte insulin receptor deficiency. Our findings identify adipocyte Gq signaling as an essential regulator of whole-body glucose and lipid homeostasis and should inform the development of novel classes of GPCR-based antidiabetic drugs. © 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.

Citation

Takefumi Kimura, Sai P Pydi, Lei Wang, Dhanush Haspula, Yinghong Cui, Huiyan Lu, Gabriele M König, Evi Kostenis, Gregory R Steinberg, Oksana Gavrilova, Jürgen Wess. Adipocyte Gq signaling is a regulator of glucose and lipid homeostasis in mice. Nature communications. 2022 Mar 29;13(1):1652