Obesity affects an ever-growing and alarming percentage of adults in developed countries. Obesity poses a major health problem since it increases the risk for such diseases as type-2 diabetes, metabolic syndrome, heart disease, and cancer. GWAS and gene deletion studies identified SH2B1 as a candidate obesity gene. Most recently, point mutations in SH2B1 have been identified in patients exhibiting severe childhood obesity and insulin resistance. Mice with targeted deletion of SH2B1 exhibit a similar phenotype (obesity, insulin resistance), suggesting an important role for SH2B1 in regulating energy intake, energy expenditure and insulin sensitivity. SH2B1 is alternatively spliced leading to 4 isoforms (?, , ?, and ?) that share an N-terminal stem region and have unique c-terminal tails. The findings that all 4 isoforms of SH2B1 are expressed in the brain and that neuronal tissue-specific expression of SH2B1 rescues the obese phenotype in mice suggest that SH2B1 plays an important function in neurons. In support of this, SH2B1 has been implicated in neurotropic factor-induced neuritis outgrowth. SH2B1 with point mutations found associated with human obesity show an impaired ability to promote neuritis outgrowth, yet the mechanism by which SH2B1 regulates neuritis outgrowth remains unclear. The overriding hypothesis is that SH2B1 affects a subset of neurotropic functions in neurons that are critical for human energy balance;a subset of functions is impaired in the obese patients with point mutations in SH2B1. This proposal will test the specific hypotheses that 1) SH2B1 isoforms enhance a specific subset of neurotropic factor-induced signaling pathways important for neuritis outgrowth;2) the human mutations impair a subset of these pathways;3) the unique SH2B1? tail provides a mechanism for regulating the ability of ? to regulate neurotropic induced neuritis outgrowth, and 4) SH2B1 is required for POMC neurons to make the proper connections in the brain.
The specific aims are: 1) to determine the neurotropic signaling pathways that are enhanced by SH2B1 but to a lesser extent by SH2B1 containing the human mutations associated with human obesity;and 2) determine how the unique tail of SH2B1? regulates SH2B1 enhancement of neuronal function. The proposed research will provide insight at the molecular and cellular level into the role of SH2B1 in the function of neurotropic factors that utilize SH2B1 as a signaling protein and at the level of the whole animal, whether SH2B1 increases the ability of neurons involved in energy expenditure to make the appropriate connections. Because of the human phenotype with genetic mutations in SH2B1, such insight should increase the understanding of cellular pathways and functions that lead to obesity and insulin resistance in humans.
The multifunctional scaffolding protein, SH2B1, has recently been identified as a human disease gene associated with obesity, insulin resistance, and in some patients, maladaptive behavior. The studies in this proposal will provide critical insight int how different isoforms of SH2B1 function at the cellular and molecular level and how mutations in SH2B1 that is associated with human disease affect that function. Understanding how mutations in SH2B1 disrupt cellular function will help us to identify essential, novel cellular proteins and functions that contribute to obesity, diabetes, and maladaptive behavior, which are prominent, ongoing public health and safety concerns.