INSR and Insulin resistance: However, during chronic overfeeding, NPY gene expression in the arcuate nucleus is paradoxically elevated [46] as a consequence of hyperinsulinemia-mediated alterations in insulin receptor and insulin-signalling pathways potentiating “central insulin resistance.” Activation of NPY neurons promotes potent orexigenic effects via increased sympathetic outflow to the liver resulting in hepatic insulin resistance and increased endogenous glucose production.