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- Title
Effects of Physiologic Increases of Circulating Adiponectin Concentrations on AMP Kinase (AMPK)/Acetyl-CoA Carboxylase (ACC) Signaling and Metabolic Indices in a Rat Model of Polygenic Obesity and Insulin Resistance.
- Authors
Swarbrick, Michael M.; Stanhope, Kimber L.; Graham, James L.; Havel, Peter J.
- Abstract
Low circulating levels of adiponectin are associated with insulin resistance (IR) and hyperlipidemia. Adiponectin-deficient mice exhibit IR, and adiponectin treatment lowers hepatic glucose production and increases fatty acid oxidation in liver and skeletal muscle by activating ACC via AMPK. We have extensive data comparing the progression of insulin resistance in Sprague-Dawley rats with polygenic, adult-onset obesity with nonobese rats. Compared to nonobese animals, the obese rats are hyperphagic, metabolically efficient, and develop IR and obesity by 3-6 months of age. At 1 month of age, however, visceral adiposity is already increased and circulating adiponectin levels are reduced, suggesting that visceral adiposity and/or decreased adiponectin may be initiating factors for the development of IR. To test this hypothesis, an interventional study was conducted to produce physiologically-relevant increases of plasma adiponectin in the obese rats over the periods of 1 to 3 months and 3 to 6 months of age to match levels present in nonobese rats. Adiponectin concentrations were increased in obese rats by administration of pioglitazone, a PPAR-gamma agonist (10 mg/kg BW/day). Prior to treatment at 1 month of age, plasma adiponectin concentrations were 4.54 ± 1.2 µg/ml and 4.4 ± 0.5 µg/ml in the control and treatment groups (n=10 per group). Pioglitazone treatment induced a stable and consistent doubling of plasma adiponectin concentrations to ∼9 µg/ml for the duration of the interventions. Elevation of adiponectin normalized several metabolic parameters. Fasting plasma free fatty acids (p< 0.001) and trigiycerides (p< 0.05) were decreased from 2 to 6 months of treatment. Fasting plasma insulin was decreased at 4 months (p<0.05). Phosphorylated ACC (Ser79) and AMPK (Thr172) in liver and skeletal muscle were quantified by Western blots. Phosphorylated ACC levels in both liver and muscle were increased by 1.5-1.6-fold in treated relative to control animals at 3 and 6 months (p<0.05). However, phosphorylated AMPK in these tissues was not significantly altered. These results suggest that physiologic increases of adiponectin levels in obese rats improves insulin resistance and hyperlipidemia possibly by. increasing fat oxidation via activation of ACC. Whether this activation of ACC requires or is independent of activation/pbosphorylation of AMPK remains to be determined. ADA-Funded Research
- Publication
Diabetes, 2007, Vol 56, pA377
- ISSN
0012-1797
- Publication type
Academic Journal