The Role of Pik3r1 in the Regulation of Adipose Tissue Insulin Sensitivity
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Date
2018-09-06
Authors
Clayton, Zachary
Journal Title
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Publisher
University of Oregon
Abstract
Obesity is a burgeoning health crisis in the United States. Obesity is associated with an earlier and greater risk for developing metabolic diseases. Insulin resistance is a central and defining feature of the metabolic diseases associated with obesity.
Class 1a Phosphatidylinositol 3-kinase (PI3K) is integral in canonical insulin signaling. PI3K contains regulatory (p85/, p55/, p50) and catalytic (p110//) subunits. The regulatory subunits are encoded by Pik3r1. Increased Pik3r1 abundance has been observed in obese white adipose tissue (WAT). Furthermore, obese mice with heterozygous (HZ) knockout of Pik3r1 remain insulin sensitive, despite marked obesity.
Taken together, it is crucial to understand the role of WAT Pik3r1 in regulating insulin sensitivity. Recently, literature has demonstrated that standard vivarium temperature (~22C) is a thermal stress for mice, as their thermoneutral zone is ~30C. Considering mice are a preclinical model for studying metabolic disease, it is critical to understand cellular and systemic responses to high fat diet (HFD) at 22C and 30C.
To determine the role of AT Pik3r1 in regulating insulin sensitivity, mice with constitutive and inducible adipocyte specific hetero/homozygous knockout of Pik3r1 were studied following acute (three days) and chronic (12 week) HFD, respectively. Furthermore, insulin sensitivity was assessed in mice with adipocyte specific overexpression (OX) of p55. To determine the influence of short-term (8 and 12 days) thermoneutral housing on insulin sensitivity, mice were studied following one and five days of HFD at 22C and 30C (one week acclimation at 30C prior to starting HFD).
Visceral WAT p85 abundance was increased (2-fold) following acute HFD in wild-type mice, with a parallel increase in systemic insulin resistance. HZ knockout of adipocyte Pik3r1 prevented acute HFD induced systemic insulin resistance. Furthermore, HZ knockout of adipocyte Pik3r1 reversed obesity induced glucose intolerance and enhanced systemic insulin sensitivity and adipocyte insulin signaling. Moreover, OX of adipocyte p55 enhanced (40%) glucose tolerance, energy expenditure (30%: light cycle; 45%: dark cycle) and markers of AT thermogenesis in brown AT. Lastly, housing temperature had a significant impact on the cellular pathways that regulate glucose metabolism in response to HFD exposure. This dissertation includes previously published co-authored material.