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ENDOCRINE PHYSIOLOGY AND METABOLISM

High-fat feeding increases insulin receptor and IRS-1 coimmunoprecipitation with SOCS-3, IKK/β phosphorylation and decreases PI-3 kinase activity in muscle

Exercise Biochemistry Laboratory, Department of Kinesiology, California State University Northridge, Northridge, California

Submitted 18 February 2009 ; accepted in final form 16 April 2009

Suppressor of cytokine signaling (SOCS) proteins and/or activation of the proinflammatory pathway have been postulated as possible mechanisms that may contribute to skeletal muscle insulin resistance. Thus, the aims of the present investigation were to determine in high-fat-fed skeletal muscle: 1) whether SOCS-3 protein concentration is increased, 2) whether coimmunoprecipitation of SOCS-3 with the insulin receptor-β subunit and/or IRS-1 is increased, and 3) whether select components of the proinflammatory pathway are altered. Thirty-two male Sprague-Dawley rats were assigned to either control (CON, n = 16) or high-fat-fed (HF, n = 16) dietary groups for 12 wk and then subjected to hind limb perfusions in the presence (n = 8/group) or absence (n = 8/group) of insulin. Insulin-stimulated skeletal muscle 3-MG transport rates and PI-3 kinase activity were greater (P < 0.05) in CON. IRS-1 tyrosine phosphorylation was decreased (P < 0.05), and IRS-1 serine 307 phosphorylation was increased (P < 0.05) in HF. Insulin receptor-β (IR-β) subunit coimmunoprecipitation with IRS-1 was reduced in HF. SOCS-3 protein concentration and SOCS-3 coimmunoprecipitation with both the IR-β subunit and IRS-1 was increased (P < 0.05) in HF. IKK/β serine phosphorylation was increased (P < 0.05), IB protein concentration was decreased (P < 0.05) and IB serine phosphorylation was increased (P < 0.05) in HF. Increased colocalization of SOCS-3 with both the IR-β subunit and IRS-1 may provide steric hindrance that prevents IRS-1 from interacting with IR-β, while increased IKKβ serine phosphorylation may contribute to increasing IRS-1 serine phosphorylation, both of which independently can have deleterious effects on insulin-stimulated PI-3 kinase activation in high-fat-fed rodent skeletal muscle.

insulin resistance; insulin signaling; proinflammatory signaling