Premium
Adipocyte Specific Expression of the PI3 Kinase Regulatory Subunit p85α Causes Reduced Insulin Sensitivity in Mice
Author(s) -
Hetrick Byron,
Clayton Zach,
Chick Wallace S.,
McCurdy Carrie
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.lb396
Subject(s) - adipocyte , adipose tissue , white adipose tissue , medicine , endocrinology , downregulation and upregulation , insulin resistance , kinase , biology , insulin receptor , adipose tissue macrophages , protein kinase b , insulin , microbiology and biotechnology , chemistry , signal transduction , biochemistry , gene
Obese adipose tissue is characterized by reduced insulin response and elevated, persistent inflammation. Obese adipose tissue has also been shown to have increased abundance of the regulatory subunits of Phosphoinsoitide 3‐kinase (PI3 kinase), p85α, p55α, and p50α. Preventing the upregulation of the PI3 kinase regulatory subunits in response to high fat diet improved insulin response and reduced inflammation in white adipose tissue. p85α contains unique N‐terminal adaptor regions that allows its function outside of regulation of PI3 kinase localization and activity. We therefore hypothesize that p85α upregulation plays a unique role contributing to insulin resistance in obese adipose tissue. To understand how adipocyte specific increases in p85α influence insulin response, we have generated a mouse model overexpressing the PI3 kinase regulatory subunit, p85α, in an adipocyte specific manner. Expression of Cre recombinase is under control of the adiponectin promoter, restricting its expression to white and brown adipocytes. Cre mediated recombination results in overexpression of p85α under control of the constitutive ROSA26 promoter. We observe overexpression of p85α specifically in white adipose tissue. In oral glucose tolerance tests, mice overexpressing p85α show an increased glucose area under the curve. Reduced adipocyte insulin response, or increased inflammation caused by adipocyte p85α overexpression may contribute to the reduced glucose tolerance. We are investigating how adipocyte specific p85α overexpression influences adipose tissue insulin response through modulation of PI3 kinase/Akt signaling pathway in response to insulin. Increased p85α expression may alter PI3 kinase activity, in addition, p85α has been shown to stabilize and activate Phosphatase and tensin homolog (PTEN), which acts in opposition to PI3 kinase to attenuate the PI3K/Akt signal transduction pathway. Besides the direct interactions in the insulin signal transduction cascade, blocking the obesity induced upregulation of PI3 kinase regulatory subunits attenuated the pro‐inflammatory environment of obese adipose tissue. We therefore also predict that p85α overexpression will increase the pro‐inflammatory gene expression profile of adipose tissue through currently unidentified pathways. Based on our observations in an adipocyte specific p85α overexpression mouse line, we propose that high fat diet induced upregulation of p85α is a pathogenic rather than adaptive response to overnutrition. Blocking high fat diet induced upregulation of p85α would likely be an effective strategy to attenuate high fat diet induced insulin resistance. Support or Funding Information NIH DK095926‐01 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .