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Growth Hormone Regulation of p85 Expression and Phosphoinositide 3-Kinase Activity in Adipose Tissue

Mechanism for Growth Hormone–Mediated Insulin Resistance

¹ Department of Internal Medicine, University of Virginia, Charlottesville, Virginia
² Department of Pediatrics, University of Colorado Health Sciences Center, Aurora, Colorado
³ Research Service, Denver Veterans Affairs Medical Center, Denver, Colorado
⁴ Department of Medicine, University of Colorado Health Sciences Center, Aurora, Colorado
⁵ Department of Obstetrics and Gynecology, University of Colorado Health Sciences Center, Aurora, Colorado
⁶ Edison Biotechnology Institute and the Department of Biomedical Sciences, Ohio University, Athens, Ohio

Address correspondence and reprint requests to Michael O. Thorner, Department of Medicine, University of Virginia, Box 800466, Charlottesville, VA 22908. E-mail: mot{at}virginia.edu. Or Juan-Pablo del Rincon, Department of Medicine, University of Virginia, Box 801411, Charlottesville, VA 22908. E-mail: jd3v{at}virginia.edu

Abbreviations: DMEM, Dulbecco's modified Eagle's medium; GH, growth hormone; IRS, insulin receptor substrate; PI, phosphoinositide; SOCS, suppressor of cytokine signaling; TBST, Tris-buffered saline with Tween; WAT, white adipose tissue

Phosphoinositide (PI) 3-kinase is involved in insulin-mediated effects on glucose uptake, lipid deposition, and adiponectin secretion from adipocytes. Genetic disruption of the p85 regulatory subunit of PI 3-kinase increases insulin sensitivity, whereas elevated p85 levels are associated with insulin resistance through PI 3-kinase–dependent and –independent mechanisms. Adipose tissue plays a critical role in the antagonistic effects of growth hormone (GH) on insulin actions on carbohydrate and lipid metabolism through changes in gene transcription. The objective of this study was to assess the role of the p85 subunit of PI 3-kinase and PI 3-kinase signaling in GH-mediated insulin resistance in adipose tissue. To do this, p85 mRNA and protein expression and insulin receptor substrate (IRS)-1–associated PI 3-kinase activity were measured in white adipose tissue (WAT) of mice with GH excess, deficiency, and sufficiency. Additional studies using 3T3-F442A cells were conducted to confirm direct effects of GH on free p85 protein abundance. We found that p85 expression 1) is decreased in WAT from mice with isolated GH deficiency, 2) is increased in WAT from mice with chronic GH excess, 3) is acutely upregulated in WAT from GH-deficient and -sufficient mice after GH administration, and 4) is directly upregulated by GH in 3T3-F442A adipocytes. The insulin-induced increase in PI 3-kinase activity was robust in mice with GH deficiency, but not in mice with GH excess. In conclusion, GH regulates p85 expression and PI 3-kinase activity in WAT and provides a potential explanation for 1) the insulin hypersensitivity and associated obesity and hyperadiponectinemia of GH-deficient mice and 2) the insulin resistance and associated reduced fat mass and hypoadiponectinemia of mice with GH excess.

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