Fat But Healthy

Abstract

Resveratrol is a polyphenolic compound produced by plants and found in red wine. It has been reported to extend life span in various model organisms, presumably through its ability to stimulate the deacetylase activity of sirtuins (there are seven isoforms in mammals, SIRT1 through 7). Baur et al . report that in mice, the addition of resveratrol to a high-calorie, high-fat diet (HCR) prevented much of the aging and disease associated with obesity without affecting body weight. Mice fed the HCR diet showed increased life span compared with high-calorie, high-fat diet (HC)-fed mice, and longevity was similar to that of mice on a standard diet. HCR mice exhibited greater insulin sensitivity and decreased circulating concentrations of glucose, insulin, and insulin-like growth factor 1 (IGF-1). The activity of adenosine monophosphate-activated protein kinase (AMPK), which is a crucial regulator of metabolism, was increased to a greater extent in the livers of the HCR-fed mice than in the livers of the HC-fed mice. Histology and assessment of various markers for the function of liver, pancreas, and heart indicated that the HCR diet prevented the damage associated with obesity. Acetylation of PGC-1α (peroxisome proliferator-activated receptor γ coactivator 1α) was decreased in the livers of the HCR-fed mice. PGC-1α is a substrate for SIRT1, and its acetylation status is used as a measure of SIRT activity. Parametric analysis of gene set enrichment (PAGE), a computational method for analyzing microarray data, suggested that resveratrol affected 127 biochemical and signaling pathways. Notable were the down-regulation of genes associated with insulin signaling and metabolism and the up-regulation of genes associated with STAT3 (signal transducer and activator of transcription 3) signaling. STAT3 signaling declines with age and may contribute to liver regeneration. Although it would obviously be best to limit caloric intake and exercise, this study suggests that there may be pharmacological interventions that can prevent some of the diseases associated with obesity (see Kaeberlein and Rabinovitch). M. Kaeberlein, P. S. Rabinovitch, Grapes versus gluttony. Nature 444 , 280-281 (2006). [PubMed] J. A. Baur, K. J. Pearson, N. L. Price, H. A. Jamieson, C. Lerin, A. Kalra, V. V. Prabhu, J. S. Allard, G. Lopez-Lluch, K. Lewis, P. J. Pistell, S. Poosala, K. G. Becker, O. Boss, D. Gwinn, M. Wang, S. Ramaswamy, K. W. Fishbein, R. G. Spencer, E. G. Lakatta, D. Le Couteur, R. J. Shaw, P. Navas, P. Puigserver, D. K. Ingram, R. de Cabo, D. A. Sinclair, Resveratrol improves health and survival of mice on a high-calorie diet. Nature 444 , 337-342 (2006). [PubMed]