The role of insulin receptor substrate signalling pathways in the regulation of energy homeostasis

Leptin and insulin act as adiposity signals signalling in the brain to regulate energy homeostasis. However, in contrast to leptin, the precise details of the cell types and signalling pathways involved in the actions of insulin have not been well defined. The dominant view in the field at the commencement of this work was largely extrapolated from studies on leptin action. It was therefore suggested that insulin exerted its effects on energy balance by inhibiting orexigenic NPY/AgRP and activating anorexigenic POMC/CART neurons of the arcuate nucleus region of the hypothalamus, thereby co-ordinately regulating energy homeostasis. Mouse genetic studies have demonstrated that insulin receptor substrate (IRS) 2, a major downstream effector of insulin signalling, plays a key role in the regulation of glucose and energy homeostasis. Mice lacking Irs2 in all tissues exhibit insulin resistance, hyperglycaemia and (3-cell failure. In addition, Irs2 null female mice are hyperphagjc, obese and infertile. However, the precise contribution of CNS IRS2 signalling in the actions of insulin and leptin, and the identity of the neuronal circuits in which IRS2 acts to regulate energy homeostasis, are unclear. The PI3K signalling pathway has been implicated in mediating the effects of insulin and leptin, in part acting downstream of IRS signalling. However, the precise hypothalamic cell types in which PI3K signalling acts also remain to be defined. To address these issues, mice with deletion of Irs2 in all neurons (NesCreIrs2KO POMC neurons (POMCCreIrs2KO) and AgRP neurons (AgRPCreIrs2KO) were generated. Animals lacking the PI3K pi 10(3 catalytic subunit in POMC (POMCCrepllOfiKO) and AgRP neurons (AgRPCrepllOfiKO) were also generated. NesCreIrs2KO animals were obese, hyperphagic and long, suggesting altered melanocortin function. Despite hyperleptinaemia, NesCreIrs2KO animals were leptin sensitive suggesting that IRS2 pathways are not required for leptin action. Reproductive function in NesCreIrs2KO females was normal. In addition, NesCreIrs2KO mice displayed hyperglycaemia, mild glucose intolerance and hyperinsulinaemia. In contrast, POMCCreIrs2KO and AgRPCreIrs2KO mice exhibited normal hypothalamic function and glucose homeostasis. AgRPCrepl 10/3KO mice were lean and hypophagic. Conversely, POMCCrepllOfiKO animals demonstrated increased adiposity and are hyperphagia. Taken together, these studies highlight a key role for CNS IRS2 pathways in the regulation of energy homeostasis but demonstrate that CNS IRS2 pathways act in neuronal populations distinct from POMC and AgRP/NPY neurons to regulate energy homeostasis. In contrast, pllOp-mediated signals in POMC and AgRP neurons play a key role in the regulation of energy homeostasis. Overall, these studies have provided new insights into the role insulin receptor substrate signalling mechanisms in the hypothalamic regulation of energy homeostasis