<b>NMDA Receptors in POMC Neurons Connects Exercise with Insulin Sensitivity</b>

Abstract

<p dir="ltr"><b>Abstract</b></p><p dir="ltr">Increased arcuate proopiomelanocortin (POMC) neuron activity improves glucose metabolism and reduces appetite, facilitating weight loss. We recently showed that arcuate POMC neurons are activated by exercise. However, the role of excitatory glutamatergic input in these neurons and the metabolic outcomes of exercise remains undefined. To investigate this, we developed a mouse model with NMDA receptors (NMDARs) selectively deleted from POMC neurons of adult mice. We performed metabolic assessments, including the monitoring of body weight, body composition analysis, and glucometabolic tolerance tests. We also examined the metabolic outcomes of these mice in response to exercise, including changes in arcuate POMC neuronal activity and insulin sensitivity. Loss of NMDARs in POMC neurons failed to alter body weight or body composition. Notably, however, we did observe a marked impairment in glucose tolerance and insulin sensitivity. Additionally, exercise resulted in activation of arcuate POMC neurons and a sustained improvement in insulin sensitivity, an effect that was abrogated in mice deficient for NMDARs in POMC neurons when compared to their respective sedentary controls. This underscores an important link between exercise, hypothalamic neuron function, and metabolic health. Moreover, this highlights an underappreciated role of hypothalamic POMC neurons in mediating exercise's beneficial effects on glucose metabolism.</p><p><br></p><p dir="ltr">Highlights</p><p dir="ltr">· High intensity interval exercise (HIIE) causes a sustained improvement in insulin sensitivity.</p><p dir="ltr">· Melanocortin neurons are required for increasing insulin sensitivity following HIIE.</p><p dir="ltr">· NMDARs in POMC neurons are necessary for improved insulin sensitivity after HIIE.</p><p dir="ltr">· Activation of arcuate POMC neurons following HIIE relies upon NMDARs.</p>