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Publication
G Protein-Coupled Receptor 17 (Gpr17) Enhances Leptin and Insulin Sensitivity in
Lean and Obese Mouse Models.
Authors Sun X, Mahler C, Stull ND, Nasiri A, Zhou B, Samuel V, Shulman G, Flak JN, Ren H
Submitted By Submitted Externally on 5/18/2026
Status Published
Journal Obesity (Silver Spring, Md.)
Year 2026
Date Published 5/13/2026
Volume : Pages Not Specified : Not Specified
PubMed Reference 42130095
Abstract Obesity, a major driver for diabetes development, is characterized by insulin
and leptin resistance. We previously showed that loss of G protein-coupled
receptor 17 (Gpr17) in specific hypothalamic neurons and the intestine led to
better energy balance and glucose metabolism. Our goal is to test whether
general loss of Gpr17 enhances insulin and leptin sensitivity., We generated
germline Gpr17 knockout mice on both lean (Gpr17-/-) and obese (Gpr17-/-; ob/ob)
backgrounds and characterized their metabolic profile., Gpr17-/- mice exhibited
increased energy expenditure and oxygen consumption. Euglycemic-hyperinsulinemic
clamp studies showed enhanced insulin sensitivity in Gpr17-/- mice with
increased glycogen synthesis and decreased glycolysis. Gpr17-/- ob/ob mice had
increased insulin sensitivity with lower baseline serum insulin and higher
response to exogenous leptin treatment with more reduction in feeding and
increased pStat3 activation in hypothalamic nuclei., These findings highlight
the inhibitory effect of Gpr17 in leptin and insulin sensitivity, suggesting its
potential as a therapeutic target for obesity treatment.




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