Basic nutritional investigationEnergy restriction does not prevent insulin resistance but does prevent liver steatosis in aging rats on a Western-style diet
Introduction
Energy restriction (ER) is reported to extend life span by up to 50% in rodents [1], [2]. Although the mechanisms implicated are not fully understood, some hypotheses have emerged [3], [4], [5], [6]: ER may prevent or delay metabolic changes occurring during aging, especially in lipids. Several age-induced metabolic changes such as impaired mitochondrial energy metabolism [7] and increased hepatic de novo lipogenesis [8] lead to tissue fat accumulation that could contribute to age-induced insulin resistance (IR) [9]. By activating a serine kinase cascade, fat accumulation could impair insulin signaling and therefore lead to decreased glucose transport in skeletal muscle and impaired glucose production by the liver [10], [11], [12]. ER improves insulin sensitivity during aging [13], [14], which may be linked to lower age-dependent fat accumulation [15], [16], [17]. ER also up-regulates some metabolic pathways in the liver, including gluconeogenesis, fatty acid β-oxidation, and ketogenesis [13], [18].
Over the past few decades, dietary habits in Western countries have evolved toward higher sugar and lower ω-3 polyunsaturated fatty acid (PUFA) intakes both of which promote IR and lipogenesis and may contribute to the development of obesity, diabetes, and fatty liver, as described both in humans and rodent models [19], [20], [21]. In rats consuming a Western-style diet, we questioned whether ER might mitigate changes in metabolites and lipids. Rats are a widely studied animal model and have the advantage of exhibiting some of the same physiological responses to ER as observed in humans. Our focus was on metabolites in liver and skeletal muscle, two insulin-sensitive organs that are important in lipid and glucose metabolism. Some liver and skeletal muscle metabolites were assessed on tissue biopsies by high-resolution magic angle spinning 1H-nuclear magnetic resonance (HRMAS 1H-NMR) spectroscopy. Plasma and tissue fatty acid profiles were analyzed by capillary gas chromatography (GC). We aimed to evaluate the effects of aging on a Western-style diet by comparing metabolite and fatty acid profiles in 2 and 19 mo old rats fed ad libitum; and to determine if ER mitigates the effect of a lifelong Western-style diet by comparing metabolite and fatty acid profiles of 19 mo old rats either fed ad libitum or subjected to a 40% ER from 7.5 to 19 mo of age.
Section snippets
Animals
Four-wk-old male Sprague-Dawley rats (Charles River, St-Constant, Quebec, Canada) were part of the Quebec Aging Research Network rat colony and were housed individually in the animal care facility of the University of Montréal. Three groups were studied: group 1, 2-mo-old rats fed ad libitum (2 AL; n = 8); group 2, 19-mo-old rats fed ad libitum (19 AL; n = 5); and group 3, 19-mo-old animals subjected to 40% ER from the age of 7.5 to 19 mo (19 ER; n = 8) [22].
All rats were initially placed on a
Body weight and insulin resistance
At the time of sacrifice, 2 AL rats weighed 335 ± 28 g, the 19 AL animals weighed 1102 ± 79 g, and the 19 ER rats weighed 595 ± 84 g. The 19 AL rats were 88% heavier than the 19 ER rats (P = 0.004), despite similar growth curves from 1 to 7.5 mo in both groups (growth rate: 24.9 ± 2.9 g/wk). Aging did not influence fasting plasma glucose; however, 19 AL rats had a 9.3-fold higher insulin-to-glucose ratio than 2 AL rats (P = 0.015) (Fig. 1A). In liver, 19 AL rats had 18.4-fold higher relative
Aging on a Western-style diet
Aging on a Western-style diet led to higher systemic IR, as indicated by higher plasma insulin or glucose. Aging is related to IR in humans and rodents [9]. The ad libitum diet used in this study also may have contributed to higher systemic IR because both ω-3 PUFA deficiency and high sucrose intake promote IR [21]. The fructose in sucrose is highly extracted by liver, where its metabolism independent of insulin is more efficient than for glucose as the former does not face the glucokinase- or
Conclusion
While on a sucrose-rich, ω-3 PUFA-poor diet, aged rats were insulin resistant and showed higher lipid accumulation in plasma and tissues compared with young rats, especially in TG and cholesteryl esters, in accordance with what is observed in humans aging on a Western-style diet. In this specific dietary context, long-term ER did not prevent systemic IR or changes in plasma and skeletal muscle metabolites in aged rats. Nevertheless, in the liver, long-term ER did prevent steatosis and changed
Acknowledgments
The authors acknowledge Guylaine Ferland and Pierrette Gaudreau for maintenance of the 19 AL and 19 ER rats. The authors also acknowledge Julie Bédard, Gérard Raffard, and Jacques Rousseau for generous support and technical assistance.
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This study was financially supported by the Fonds de recherche du Québec-Santé (FRQS), Natural Sciences and Engineering Research Council of Canada (NSERC) (3606-2008), Canadian Foundation for Innovation (CFI), Université de Sherbrooke (SCC's University Chair) and the Quebec Network for Research on Aging. SCC, and MR conceived and designed the experiments. MH, MR, VSP, ACL, MCB, AKBS, JLG, and MF performed the experiments and analyses. MH and MR analyzed the data. All the authors contributed to writing and revising the article.