Abstract

Obejctive– The sites of insulin action in the central nervous system that regulate glucose metabolism and energy expenditure are incompletely characterized. We have shown that mice with hypothalamic deficiency (L1) of insulin receptors (InsR) fail to regulate hepatic glucose production (HGP) in response to insulin.

Research Design And Methods– To distinguish neurons that mediate insulin's effects on HGP from those that regulate energy homeostasis, we used targeted knock-ins to express InsR in AgRP or POMC neurons of L1 mice.

Results– Restoration of insulin action in AgRP neurons normalized insulin suppression of HGP. Surprisingly, POMC-specific InsR knock-in increased energy expenditure and locomotor activity, exacerbated insulin resistance and increased HGP, associated with decreased expression of the K_ATP channel SUR1 subunit and decreased inhibitory synaptic contacts on POMC neurons.

Conclusions– The contrasting phenotypes of InsR knock-ins in POMC and AgRP neurons suggest a branched-pathway model of hypothalamic insulin signaling, in which InsR signaling in AgRP neurons decreases HGP, while InsR activation in POMC neurons promotes HGP and activates the melanocortinergic energy expenditure program.