PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance
Sean M. Crosson, Ahmir Khan, John Printen, Jeffrey E. Pessin, Alan R. Saltiel
Sean M. Crosson, Ahmir Khan, John Printen, Jeffrey E. Pessin, Alan R. Saltiel
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Article Metabolism

PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance

Abstract

Protein targeting to glycogen (PTG) is a scaffolding protein that targets protein phosphatase 1α (PP1α) to glycogen, and links it to enzymes involved in glycogen synthesis and degradation. We generated mice that possess a heterozygous deletion of the PTG gene. These mice have reduced glycogen stores in adipose tissue, liver, heart, and skeletal muscle, corresponding with decreased glycogen synthase activity and glycogen synthesis rate. Although young PTG heterozygous mice initially demonstrate normal glucose tolerance, progressive glucose intolerance, hyperinsulinemia, and insulin resistance develop with aging. Insulin resistance in older PTG heterozygous mice correlates with a significant increase in muscle triglyceride content, with a corresponding attenuation of insulin receptor signaling. These data suggest that PTG plays a critical role in glycogen synthesis and is necessary to maintain the appropriate metabolic balance for the partitioning of fuel substrates between glycogen and lipid.

Authors

Sean M. Crosson, Ahmir Khan, John Printen, Jeffrey E. Pessin, Alan R. Saltiel

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Reduction of PTG protein levels leads to reduced glycogen stores due to ...
Reduction of PTG protein levels leads to reduced glycogen stores due to decreased basal and insulin-stimulated glycogen synthesis. (a) PTG+/– mice display reduced glycogen stores. Glycogen levels were analyzed from tissues isolated from nonfasted 1- to 2-month-old male animals (n = 6 per group: adipose and heart; n = 7–8 per group: liver, epitrochlearis, and quadriceps; n = 3–6 per group: gastrocnemius) or from fasted 18-month-old male animals (n = 4–10 per group, liver; n = 4–12 per group, heart). Results are reported as mean ± SEM. *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.005. (b) Glycogen synthase activity ratio is decreased in insulin-responsive tissues of PTG+/– mice. Glycogen synthase activity was assayed in tissue homogenates prepared from 1- to 2-month-old male animals in the nonfasting state (n = 9 per group, adipose; n = 7–8 per group, liver). Results are reported as mean ± SEM (*P ≤ 0.002; **P ≤ 0.001). G6P, glucose-6-phosphate. (c) Basal and insulin-stimulated glycogen synthase activity ratio is decreased in skeletal muscle of PTG+/– mice. Glycogen synthase activity was assayed in homogenates of forelimb epitrochlearis muscle in the basal state and after stimulation with 2 mU/g body weight human recombinant insulin. Animals were 1- to 2-month-old males in the nonfasting state (n = 4–7 per group). Results are reported as mean ± SEM (*P ≤ 0.05; **P ≤ 0.002). (d) The levels of total cellular glycogen synthase (GS) and PP1 protein are unchanged in adipose, liver, and epitrochlearis muscle of PTG+/– mice. Total cellular levels of glycogen synthase or PP1 protein were analyzed by Western blotting of tissue homogenates prepared from 1- to 2-month-old male animals in the nonfasting state. It should be noted that the anti–skeletal muscle glycogen synthase antibody used cannot detect the liver isoform of glycogen synthase.