Submitted to: Journal of Nutritional Biochemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/4/2010
Publication Date: 2/11/2011
Citation: Marecki, J.C., Ronis, M.J., Shankar, K., Badger, T.M. 2011. Hyperinsulinemia and ectopic fat disposition can develop in the face of hyperadiponectinemia in young obese rats. Journal of Nutritional Biochemistry. 22(2):142-152. Interpretive Summary: Childhood obesity in the U.S. and around the world is a significant health concern, and little is known about the ways in which the excessive amounts of fat in the diet, contribute to abnormal storage of fats in the liver (fatty liver) and the muscles leading to liver damage. This could lead to the loss of insulin action, resulting in Type 2 diabetes. During the development of childhood obesity, increased fat storage in tissue results in a change in the amount of a protein known as adiponectin, which causes insulin resistance and liver disease. To study the role of insulin and adiponectin in young animals, we overfed young, male rats a diet containing high amounts of saturated and unsaturated fats, and examined the blood, the liver, and the muscle for signs of altered fat metabolism. Excessive consumption of the high fat diets led to obesity, altered amounts of adiponectin in the blood, as well as abnormal storage of fats in the liver and muscle; and altered insulin action in the muscle tissues. Our study suggests that in the development of childhood obesity, tissues respond to excessive dietary fats by increasing the import of circulating fats into the liver and muscle despite an increase in the rate of burning of the tissue fats. We are currently studying the mechanisms in which excess fats in the tissues lead to altered insulin action, focusing on ways to prevent the early detrimental effects of unbalanced, high fat diets that contribute to childhood obesity.
Technical Abstract: Serum adiponectin has been reported to inversely correlate with the degree of adiposity in children. However, the relative contribution of adiponectin-dependent signaling, to the development of ectopic fat deposition and insulin resistance in childhood obesity is unclear. We investigated the role of adiponectin in prepubertal, male Sprague-Dawley rats, overfed a high fat diet via total enteral nutrition. Excessive caloric intake led to clinical characteristics of obesity, including increased body weight and fat mass; dyslipidemia; ectopic fat deposition; and hyperinsulinemia (P < 0.05). Expression of the fatty acid transporter FAT/CD36 was elevated in both liver and skeletal muscle of these rats (Pless than 0.05). Akt phosphorylation in liver was elevated (P < 0.05) and FoxO1 protein in hepatic nuclear extracts was reduced (P < 0.05) in the face of hyperinsulinemia; whereas, no increase in Akt phosphorylation was observed in skeletal muscle. Overfeeding increased serum adiponectin concentration from 24.6 +/- 1.9 ug/ml to 46.3 +/- 5.9 ug/ml (P < 0.004), and positively correlated with increased adipose tissue mass. The expression of the inflammatory cytokine TNF-alpha in the adipose tissue was unchanged. Adiponectin-mediated AMP kinase phosphorylation, PPAR-alpha expression and the expression of genes involved in fatty acid oxidation were elevated in insulin-sensitive tissues (P < 0.05). These data: 1) demonstrate that excessive intake of a high fat diet in young rats results in adiponectin-independent increases in peripheral insulin resistance and elevated ectopic fat deposition; 2) suggest that fatty acid transport is a major mechanism underlying ectopic fat deposition; and 3) raise interesting issues regarding potential age-related differences in the role of adiponectin in pathological responses associated with obesity.