Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis

Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although Irs4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because Irs4-null mice barely distinguishable from controls. We postulated that Irs2 and Irs4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body Irs4−/y mice that lacked Irs2 in the CNS (bIrs2−/−·Irs4−/y) or only in LepRb-neurons (Lepr∆Irs2·Irs4−/y). bIrs2−/−·Irs4−/y mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr∆Irs2·Irs4−/y mice were not different from Lepr∆Irs2 mice, suggesting that the functions of Irs2 and Irs4 converge upon neurons that are distinct from those expressing LepRb.