High-Fat-Diet-Induced Obesity and Heart Dysfunction Are Regulated by the TOR Pathway in Drosophila

NASCR Center, Sanford/Burnham Medical Research Institute, La Jolla, CA 92037, USA.
Cell metabolism (Impact Factor: 16.75). 11/2010; 12(5):533-44. DOI: 10.1016/j.cmet.2010.09.014
Source: PubMed

ABSTRACT High-fat-diet (HFD)-induced obesity is a major contributor to diabetes and cardiovascular disease, but the underlying genetic mechanisms are poorly understood. Here, we use Drosophila to test the hypothesis that HFD-induced obesity and associated cardiac complications have early evolutionary origins involving nutrient-sensing signal transduction pathways. We find that HFD-fed flies exhibit increased triglyceride (TG) fat and alterations in insulin/glucose homeostasis, similar to mammalian responses. A HFD also causes cardiac lipid accumulation, reduced cardiac contractility, conduction blocks, and severe structural pathologies, reminiscent of diabetic cardiomyopathies. Remarkably, these metabolic and cardiotoxic phenotypes elicited by HFD are blocked by inhibiting insulin-TOR signaling. Moreover, reducing insulin-TOR activity (by expressing TSC1-2, 4EBP or FOXO), or increasing lipase expression-only within the myocardium-suffices to efficiently alleviate cardiac fat accumulation and dysfunction induced by HFD. We conclude that deregulation of insulin-TOR signaling due to a HFD is responsible for mediating the detrimental effects on metabolism and heart function.

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Available from: Karen Ocorr, Aug 15, 2015
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    • "Although the correlation between temperature and heart rate has been demonstrated in several insect orders, most of what we know about the effect of diet on heart physiology comes from studies done on the fruit fly, Drosophila melanogaster. In this fly species, balanced low calorie diets result in lower myocardial lipid levels and increased cardiac performance (Bazzell et al., 2013; Birse et al., 2010; Lim et al., 2011), whereas diets that are high in sugar induce cardiomyopathy (Na et al., 2013). In Periplaneta americana nymphs, food deprivation does not induce noticeable changes in heart physiology, but food deprivation in aquatic Anopheles quadrimaculatus larvae results in a decrease in the heart rate (Jones, 1956, 1977). "
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    • "Most of the commensal bacteria of the fruit fly are cultivable in vitro, which facilitates experimental manipulations of gut microbial communities and microbial genetic analysis. Also Drosophila is one of the major insect model systems in the study of innate immunity (Hultmark, 2003; Lemaitre and Hoffmann, 2007), aging (Bjedov et al., 2010), metabolism (Bharucha, 2009; Birse et al., 2010), intestinal stem cells homeostasis (Apidianakis and Rahme, 2011; Buchon et al., 2010; Casali and Batlle, 2009), large-scale dietary studies (e.g. Lee et al., 2008) and offers substantial molecular genetic resources. There is then strong expectations that laboratory experiments on Drosophila will define future research in biomedical systems (mammals and humans), which currently lacks a framework to better understand the relationships between nutrition, immunity and gut microbial ecology at different stages of life and in distinct environments . "
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    • "Experimental diets: regular and high-fat Jazz Mix Drosophila food from New Horizon Foods was prepared as directed and placed in plastic vials as the regular diet (RD). The high-fat diet (HFD) was based on a recipe developed by Dr. Sean Oldham at the Sanford/Burnham Institute, adding coconut oil to the regular food as a source for increased saturated fat in the diet [18]. The recipe has been specialized for the current model, with coconut oil added in the amount of 20% weight per volume in the HFD (approximately 70% calories from fat) [21] "
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