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- Title
Whole-Body Overexpression of PGC-1α Has Opposite Effects on Hepatic and Muscle Insulin Sensitivity.
- Authors
Balas, Bogdan; Liang, Huiyun; Richardson, Arlan; Defronzo, Ralph A.; Ward, Walter; Musi, Nicolas
- Abstract
PGC-1α is a transcriptional coactivator which regulates adaptive responses to a variety of physiologic stimuli. In the liver, PGC-1α expression is induced by fasting, whereas in muscle, its expression is increased by exercise training. In the liver, PGC-1α regulates glucose production, while in muscle PGC-1α stimulates mitochondrial biogenesis. However, the role that PGC-1α plays in controlling whole-body insulin sensitivity is not clear. Our goal was to examine the role of PGC-1α on whole-body glucose homeostasis, using a novel transgenic (TG) mouse model that globally overexpresses PGC-1α within a physiologic range [∼2-fold higher than wildtype (WT)]. At 16-32 weeks of age, awake, unrestrained, chronically catheterized mice (n=5 TG and n=9 WT) received a euglycemic hyperinsulinemic (18 mU⋅kg-1⋅min-1) clamp with 3-3H-glucose. In liver from TG, PGC-1α overexpression resulted in enhanced gene expression of the gluconeogenic enzymes PEPCK, G6Pase and HNF-4α by 2.2-, 2.5-, and 1.5-fold, respectively (P<0.05). These enzyme changes in TG mice were associated with an increase in basal hepatic glucose production (41±6 vs. 31±2 mg⋅kg-1⋅min-1; P<0.05), and impaired suppression of hepatic glucose production by insulin (53±6 vs. 94±5%; P<0.05) versus WT. In muscle from TG, PGC-1α overexpression led to 43% and 133% increases in myoglobin and troponin I slow proteins (P<0.05), changes reminiscent to the fiber-type switching observed with physical training. Insulin-stimulated total body glucose disposal (which primarily reflects muscle) was increased in TG versus WT (132±7 vs. 117±4 mg⋅kg-1⋅min-1; P<0.05). Summary: overexpression of PGC-1α, within physiologic levels, produces dichotomous effects on liver and muscle insulin sensitivity. We postulate that PGC-1α acts as a fuel gauge which couples energy demands (muscle) with the corresponding fuel supply (liver). Thus, under conditions of physiologic stress (i.e. prolonged fast and physical training), increased hepatic glucose production may help to sustain increased glucose transport and utilization in peripheral (muscle) tissues.
- Subjects
PROTEINS; INSULIN resistance; LIVER; MUSCLES; GLUCOSE; MICE
- Publication
Diabetes, 2007, Vol 56, pA62
- ISSN
0012-1797
- Publication type
Article