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Obesity affects a significant fraction of the world population, with some states or countries reporting overwhelming majority of the population as obese or overweight. Effective treatments were not readily available until the recent approval of glucagon-like peptide-1 (GLP-1) -based pharmacotherapeutics for weight loss. Since then, the use of GLP-1-based pharmacotherapies for the treatment of obesity has skyrocketed. In addition to or because of the effective weight loss, these medications affect many different organs in the body. Many of these effects, including the degree of weight loss achieved, show significant sex differences. Moreover, recent analysis of online patient communities identified a range of self-reported reproductive and endocrine side effects of GLP-1 based therapies including menstrual irregularities, reduced libido, and hot-flashes that have not been systematically captured in clinical trials. Some of these reports contrast with recent data indicating that in Polyendocrine Metabolic Ovarian Syndrome (PMOS; formerly Polycystic Ovary Syndrome) patients semaglutide-associated weight loss normalizes menstrual cycles in most patients, leaving this issue unresolved. While it has been established that sex and sex hormones affect the action of GLP-1 analogues, whether these medications affect the levels of sex hormones and reproductive organs is less well understood, especially in a chronic and clinically relevant drug application setting.

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Loss of GIPR in glutamatergic neurons does not impair acceleration of GLP-1-induced weight loss by GIPR antagonism

Russell L. Castelino, Ahmed Khalil, Gandhari Maity-Kumar, Shiqi Zang, ... Timo D. Müller

Objective

Agonism and antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) accelerate weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. Recent studies have shown that GIPR antagonism, unlike GIPR agonism, does not rely on GIPR signaling in GABAergic neurons to enhance GLP-1-induced weight loss, suggesting that this effect instead depends on GIPR signal modification in other types of neurons. Accordingly, we here assessed whether selective loss of Gipr in glutamatergic neurons affects the ability of GIPR antagonism to enhance GLP-1-induced weight loss.

Methods

Mice with deletion of Gipr in excitatory (Vglut2-expressing) glutamatergic neurons were metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and the ability of GIPR antagonism to enhance GLP-1-induced weight loss.

Results

Mice lacking GIPR in Vglut2-expressing neurons show improved glucose tolerance despite normal development of diet-induced obesity and remain fully responsive to accelerate GLP-1-induced weight loss by GIPR antagonism.

Conclusion

Our results show that GIPR antagonism does not require GIPR signaling in Vglut2-expressing neurons to potentiate GLP-1-induced weight loss, suggesting that the GIPR expressing cells/neurons mediating this effect are neither GABAergic nor Vglut2-expressing glutamatergic.

Articles in Press

Loss of GIPR in glutamatergic neurons does not impair acceleration of GLP-1-induced weight loss by GIPR antagonism

Russell L. Castelino, Ahmed Khalil, Gandhari Maity-Kumar, Shiqi Zang, ... Timo D. Müller

Objective

Agonism and antagonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) accelerate weight loss induced by glucagon-like peptide-1 receptor (GLP-1R) agonism. Recent studies have shown that GIPR antagonism, unlike GIPR agonism, does not rely on GIPR signaling in GABAergic neurons to enhance GLP-1-induced weight loss, suggesting that this effect instead depends on GIPR signal modification in other types of neurons. Accordingly, we here assessed whether selective loss of Gipr in glutamatergic neurons affects the ability of GIPR antagonism to enhance GLP-1-induced weight loss.

Methods

Mice with deletion of Gipr in excitatory (Vglut2-expressing) glutamatergic neurons were metabolically characterized for alterations in diet-induced obesity (DIO), glucose control and the ability of GIPR antagonism to enhance GLP-1-induced weight loss.

Results

Mice lacking GIPR in Vglut2-expressing neurons show improved glucose tolerance despite normal development of diet-induced obesity and remain fully responsive to accelerate GLP-1-induced weight loss by GIPR antagonism.

Conclusion

Our results show that GIPR antagonism does not require GIPR signaling in Vglut2-expressing neurons to potentiate GLP-1-induced weight loss, suggesting that the GIPR expressing cells/neurons mediating this effect are neither GABAergic nor Vglut2-expressing glutamatergic.

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