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 and Jürgen Wess ()
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Takefumi Kimura: National Institute of Diabetes and Digestive and Kidney Diseases
Sai P. Pydi: National Institute of Diabetes and Digestive and Kidney Diseases
Lei Wang: National Institute of Diabetes and Digestive and Kidney Diseases
Dhanush Haspula: National Institute of Diabetes and Digestive and Kidney Diseases
Yinghong Cui: National Institute of Diabetes and Digestive and Kidney Diseases
Huiyan Lu: National Institute of Diabetes and Digestive and Kidney Diseases
Gabriele M. König: University of Bonn
Evi Kostenis: University of Bonn
Gregory R. Steinberg: McMaster University
Oksana Gavrilova: Mouse Metabolism Core National Institute of Diabetes and Digestive and Kidney Diseases
Jürgen Wess: National Institute of Diabetes and Digestive and Kidney Diseases

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-29231-6

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