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Metabolic and cellular effects of calorie restriction and whey proteins in experimental obesity

Year: 2013
Type: dissertation
Abstract: Obesity, an epidemic problem in the world, is associated with higher mortality and increase in the risk of diabetes, cardiovascular diseases, and certain forms of cancer. Calorie restriction (CR) with adequate nutrition is the most effective method to induce weight loss, though compliance with low-caloric diets is often poor among obese individuals. Compounds capable of mimicking the effects of CR therefore hold great promise as novel anti-obesity drugs. The main aim of the present study was to investigate the molecular and signaling pathways mediating the effects of CR with special emphasis on the sirtuin, AMPK and mTOR pathways. As data from recent clinical and experimental studies suggest, milk-derived whey proteins could enhance the anti-obesity effects of CR by yet unknown mechanisms, the study also aimed to clarify the anti-obesity effects of whey proteins and their mechanisms of action. High-fat diet induced C57Bl/6J mice were used as a model of experimental obesity. The metabolic effects of dietary regimens were examined by daily recording of food and energy intake, body weight monitoring three times weekly, in vivo calorimetry, and analysis of body fat percentage and lean body mass by dual-energy X-ray. The cellular effects were investigated by immunohistochemistry, Western blot and qRT-PCR analyses, as well as by protein arrays and microarray genechips. CR (energy intake 70% of ad libitum intake) protected against obesity and fatty liver, induced physical activity and ameliorated adipose tissue inflammation. These effects were associated with an increased SIRT1 expression in the liver and skeletal muscle as well as the SIRT3 expression in the liver, skeletal muscle and adipose tissue. CR also increased the SIRT4 expression in the skeletal muscle. In contrast, the SIRT1 activating compound resveratrol did not prevent obesity although it partially prevented fatty liver and modestly increased skeletal muscle SIRT1 and SIRT4 expressions. CR exerted distinct effects on adipose tissue cytokine and angiogenesis profiles in obese and lean mice. Obesity induced cytokine and angiogenesis-related protein expressions, and these changes were largely ameliorated by CR, while in lean mice, CR increased the expression of several cytokines and angiogenesis-related proteins. High-calcium whey protein (WPI) and α-lactalbumin diets enhanced the anti-obesity effects of CR. These diets produced marked alteration in the skeletal muscle gene expression profile compared to the casein diet, with the Wnt signaling being the most highly altered pathway. Unlike casein, WPI and α-lactalbumin diets induced SIRT3 protein expressions in muscle and decreased the Aldh1a7, Fasn, leptin, Nr4a3 and Scd1 mRNA expressions, indicating alterations in lipid and fatty acid metabolism. A novel WPI rich in lactoperoxidase, lactoferrin, growth factors and immunoglobulins dose-dependently enhanced weight loss during CR, prevented weight re-gain and protected against fatty liver formation during the ad libitum phase. WPI increased hepatic SIRT3 expressions more than casein and decreased hepatic S6 ribosomal protein phosphorylation, suggesting inhibition of the mTOR pathway. In conclusion, the present study showed that CR increases the expression of sirtuins, in particular SIRT3, in metabolically important tissues suggesting their central role as mediators of the metabolic and cellular effects of CR. The present study also provides evidence that CR ameliorates obesity-induced cytokine and angiogenesis protein overexpression in adipose tissue. Finally, the present study underlined that whey protein-based diets enhance the anti-obesity effects of CR via mechanisms linked to sirtuins and altered skeletal muscle gene expression profile.
Language: English
Field: Medicine
Open Access status: green
OpenAlex ID: W1519272196
Cites: 538
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Related to: 10