An Adipokine-Mediated Process?
Age-dependent changes in insulin action and body fat distribution are risk factors for the development of type 2 diabetes. To examine whether the accumulation of visceral fat (VF) could play a direct role in the pathophysiology of insulin resistance and type 2 diabetes, we monitored insulin action, glucose tolerance, and the expression of adipo-derived peptides after surgical removal of VF in aging (20-month-old) F344/Brown Norway (FBN) and in Zucker Diabetic Fatty (ZDF) rats. As expected, peripheral and hepatic insulin action were markedly impaired in aging FBN rats, and extraction of VF (accounting for ∼18% of their total body fat) was sufficient to restore peripheral and hepatic insulin action to the levels of young rats. When examined at the mechanistic level, removal of VF in ZDF rats prevented the progressive decrease in insulin action and delayed the onset of diabetes, but VF extraction did not alter plasma free fatty acid levels. However, the expression of tumor necrosis factor-α and leptin in subcutaneous (SC) adipose tissue were markedly decreased after VF removal (by approximately three- and twofold, respectively). Finally, extracted VF retained ∼15-fold higher resistin mRNA compared with SC fat. Our data suggest that insulin resistance and the development of diabetes can be significantly reduced in aging rats by preventing the age-dependent accumulation of VF. This study documents a cause-and-effect relationship between VF and major components of the metabolic syndrome.
Address correspondence and reprint requests to Nir Barzilai, Institute for Aging Research, Belfer Bldg. no. 701, Albert Einstein College of Medicine, 1300 Morris Park Ave., Bronx, NY 10461. E-mail:.
Received for publication 15 April 2002 and accepted in revised form 2 July 2002.
CR, caloric restriction; dsDNA, double-stranded DNA; EGP, endogenous glucose production; FFA, free fatty acid; SC, subcutaneous; TNF-α, tumor necrosis factor-α; VF, visceral fat.