Adipocyte Gi signaling is essential for maintaining whole-body glucose homeostasis and insulin sensitivity

Lei Wang, Sai P. Pydi, Lu Zhu, Luiz F. Barella, Yinghong Cui, Oksana Gavrilova, Kendra K. Bence, Cecile Vernochet and Jürgen Wess ()
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Lei Wang: National Institute of Diabetes and Digestive and Kidney Diseases
Sai P. Pydi: National Institute of Diabetes and Digestive and Kidney Diseases
Lu Zhu: National Institute of Diabetes and Digestive and Kidney Diseases
Luiz F. Barella: National Institute of Diabetes and Digestive and Kidney Diseases
Yinghong Cui: National Institute of Diabetes and Digestive and Kidney Diseases
Oksana Gavrilova: National Institute of Diabetes and Digestive and Kidney Diseases
Kendra K. Bence: Pfizer Inc
Cecile Vernochet: Pfizer Inc
Jürgen Wess: National Institute of Diabetes and Digestive and Kidney Diseases

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Adipocyte dysfunction links obesity to insulin resistance and type 2 diabetes. Adipocyte function is regulated by receptor-mediated activation of heterotrimeric G proteins. Little is known about the potential in vivo metabolic roles of Gi-type G proteins expressed by adipocytes, primarily due to the lack of suitable animal models. To address this question, we generated mice lacking functional Gi proteins selectively in adipocytes. Here we report that these mutant mice displayed significantly impaired glucose tolerance and reduced insulin sensitivity when maintained on an obesogenic diet. In contrast, using a chemogenetic strategy, we demonstrated that activation of Gi signaling selectively in adipocytes greatly improved glucose homeostasis and insulin signaling. We also elucidated the cellular mechanisms underlying the observed metabolic phenotypes. Our data support the concept that adipocyte Gi signaling is essential for maintaining euglycemia. Drug-mediated activation of adipocyte Gi signaling may prove beneficial for restoring proper glucose homeostasis in type 2 diabetes.

Date: 2020
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DOI: 10.1038/s41467-020-16756-x

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