SH2B1 Regulates Insulin Sensitivity and Glucose Homeostasis by Multiple Mechanisms.

SH2B1;Insulin Resistance;Glucose Homeostasis;Signaling;Physiology;Health Sciences;Molecular and Integrative Physiology

Morris, David L.Thompson, Robert C. ;

University of Michigan

关键词: SH2B1;    Insulin Resistance;    Glucose Homeostasis;    Signaling;    Physiology;    Health Sciences;    Molecular and Integrative Physiology;   

Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/64630/morrisdl_1.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Leptin and insulin are key hormonal regulators of energy balance and glucose homeostasis.SH2B1 is a PH- and SH2-domain containing adapter protein that promotes both leptin and insulin signaling in cells.Disruption of Sh2b1 in mice causes obesity and diabetes, providing genetic evidence that SH2B1 is an essential regulator of energy balance and glucose homeostasis.Here, the contribution of SH2B1 in brain, peripheral tissues, and islets to the regulation of insulin sensitivity and glucose homeostasis was examined in vivo.Reconstitution of full length SH2B1, but not the SH2 domain alone, in neurons in Sh2b1-deficient mice was sufficient to prevent the development of obesity and insulin resistance.By contrast, expression of a mutant form of SH2B1 that lacked a functional SH2 domain in neurons of wild type mice promoted weight gain and impaired whole body insulin sensitivity.Thus, SH2B1 in the brain indirectly regulates glucose homeostasis by controlling energy balance and body weight.To address the role of peripheral SH2B1 in the regulation of insulin sensitivity and glucose metabolism, mice expressing SH2B1 in the brain but not in peripheral tissues (TgKO mice), were fed a high fat diet (HFD).Deletion of SH2B1 in peripheral tissues did not alter HFD-induced obesity, but significantly exacerbated HFD-induced hyperglycemia, hyperinsulinemia and glucose intolerance in TgKO mice.Insulin signaling was attenuated in muscle, liver, and white adipose tissue from HFD-fed TgKO mice.In cultured cells, SH2B1 binds to the insulin receptor, IRS-1 and IRS-2, and enhances insulin sensitivity by both promoting receptor activity and by inhibiting tyrosine dephosphorylation of IRS proteins, providina mechanism by which SH2B1 likely promotes insulin action in these tissues.SH2B1 also promotes glucose homeostasis independent of central leptin action.Leptin-deficient (ob/ob) mice with Sh2b1 haploinsufficiency (Sh2b1+/-ob/ob) developed severe hyperglycemia and glucose intolerance.Plasma insulin levels and pancreatic insulin content were reduced in Sh2b1+/-ob/ob mice.SH2B1 is highly expressed in pancreatic islets, and these data suggest that SH2B1 in islets may regulate glucose homeostasis by promoting insulin biosynthesis and secretion.Together, these findings indicate that SH2B1 regulates insulin sensitivity and glucose homeostasis by multiple mechanisms in vivo.