The role of insulin receptor substrate 2 in beta cell function

Insulin receptor substrate (Irs) 2 plays complex roles in the regulation of glucose homeostasis, energy balance and CNS development. To address the tissue-specific role of Irs2 signalling events, conditional Irs2-deficient mice were generated. IrsHoxAox mice were crossed with mice expressing Cre recombinase under the control of the rat insulin II gene promoter (RIPCre mice). Deletion of Irs2 occurred in pancreatic (3 cells and in a population of hypothalamic neurons thus generating RlPCrelrslKO mice. RlPCrelrs2KO mice displayed impaired glucose tolerance, reduced beta cell mass and islet number but remained hyperinsulinaemic. Over time some recovery in islet mass was seen with islets not expressing Cre repopulating the islets. Furthermore RlPCrelrslKO mice developed a prominent hypothalamic phenotype with hyperphagia, obesity, increased body length and hyperleptinaemia. RlPCrelrslKO mice were sensitive to leptin treatment and displayed a normal metabolic rate. Characterisation of the hypothalamic neurons that express Cre recombinase revealed that they did not express pro-opiomelanocortin or neuropeptide Y. These findings therefore demonstrate a critical role for intrinsic Irs2 signalling pathways in (3-cell and hypothalamic function and give insights into novel hypothalamic neuronal populations involved in the regulation of energy homeostasis. Deleting STAT3 in the same tissues (RIPCreSTATJKO) resulted in a mouse with no (3 cell phenotype but which developed obesity. This obesity was not due to hyperphagia and was possibly due to an increase in activity, although this has not been confirmed. In addition to this, RIPCreSTAT3KO mice were sensitive to leptin treatment. These findings therefore demonstrate that STAT3 signalling pathways are not needed for normal (3-cell mass and function but that STAT3 in the hypothalamus plays an important role in body weight maintenance