Introduction and Objective: Diabetes and obesity affect millions of individuals in the United States leading to significant morbidity and mortality. Obesity, major driver for diabetes development, is characterized by insulin and leptin resistance. We previously showed that loss of Gpr17 in selective hypothalamic neurons and intestine led to better energy balance and glucose metabolism. Our goal is to test whether general loss of Gpr17 promotes insulin and leptin sensitivity.Methods: We generated whole-body Gpr17 knockout mice on lean (Gpr17 -/-) and obese (Gpr17 -/-; ob/ob) background and characterized their metabolic profile. Furthermore, we generated LepRb neuron-specific GPR17 knockout (Gpr17 -/-;Lepr-ires-Cre) mice to test the effect of Gpr17 on leptin sensitivity.Results: Whole-body Gpr17 knockout (Gpr17 -/-) mice exhibited increased energy expenditure and oxygen consumption. Euglycemic hyperinsulinemic clamp studies showed enhanced insulin sensitivity in Gpr17 -/- mice with increased glycogen synthesis, decreased glycolysis, and glucose uptake. Leptin-deficient Gpr17 knockout (Gpr17 -/-; ob/ob) mice had increased insulin sensitivity with lower baseline serum insulin and higher lipolysis. Gpr17 -/-; ob/ob mice responded to exogenous leptin injection with reduced feeding behavior and increased pStat3 activation in hypothalamic nuclei compared with ob/ob mice. LepRb neuron-specific GPR17 knockout (Gpr17 -/-;Lepr-ires-Cre) mice showed increased leptin sensitivity than control, resulting in increased energy expenditure, attenuated high-fat diet-induced hyperphagia, and reduced body weight gain under both normal and high-fat diet conditions.Conclusion: These findings highlight the role of GPR17 in regulating leptin sensitivity, suggesting its potential as a target to treat diabetes and obesity.
X. Sun: None. H. Ren: None.
R01DK120772, R00DK098294, R03TR003350, UM1TR004402
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