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: 17.57). 11/2010; 12(5):533-44. DOI: 10.1016/j.cmet.2010.09.014
Source: PubMed


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.

Download full-text


Available from: Karen Ocorr
  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult female mosquitoes rely on carbohydrate-rich plant nectars as their main source of energy. In the present study we tested whether the deprivation of a carbohydrate dietary source or the deprivation of both carbohydrate and water affects mosquito heart physiology. Intravital video imaging of Anopheles gambiae showed that, relative to sucrose fed mosquitoes, the deprivation of both sucrose and water for 24 h, but not the deprivation of sucrose alone, reduces the heart contraction rate. Measurement of the protein, carbohydrate and lipid content of mosquitoes in the three treatment groups did not explain this cardiac phenotype. However, while the deprivation of sucrose reduced mosquito weight and abdominal width, the deprivation of both sucrose and water reduced mosquito weight even further without augmenting the change in abdominal width, indirectly suggesting that starvation and dehydration reduces hemolymph pressure. Analysis of the mRNA levels of crustacean cardioactive peptide (CCAP), FMRFamide, corazonin, neuropeptide F and short neuropeptide F then suggested that these neuropeptides do not regulate the cardiac phenotype observed. However, relative to sucrose fed and sucrose deprived mosquitoes, the mRNA level of nitric oxide synthase (NOS) was significantly elevated in mosquitoes that had been deprived of both sucrose and water. Given that nitric oxide suppresses the heart rate of vertebrates and invertebrates, these data suggest a role for this free radical in modulating mosquito heart physiology. Copyright © 2015. Published by Elsevier Ltd.
    Full-text · Article · Jan 2015 · Journal of Insect Physiology
  • Source
    • "Please also see Figure S7. Immunity 42, 133–144, January 20, 2015 ª2015 The Authors 141 42%; polyunsaturated, 9.5%; salt, nil; fiber, nil; Sainsbury's Basics Lard) in a weight-for-volume manner as described by Birse et al. (Birse et al., 2010), at either 6.3% or 15%. All experiments were carried out using the 15% lardenriched diet except for experiments shown in Figures 3B and 3D, where a 6.3% lard-enriched diet was used. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic activation of JAK-STAT signaling, reduced insulin sensitivity, hyperglycemia, and a shorter lifespan. Drosophila macrophages produced the JAK-STAT-activating cytokine upd3, in a scavenger-receptor (crq) and JNK-dependent manner. Genetic depletion of macrophages or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-κB signaling made no contribution to the phenotype observed. These results identify an evolutionarily conserved "scavenger receptor-JNK-type 1 cytokine" cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
    Full-text · Article · Dec 2014 · Immunity
  • Source
    • "For glucose measurements [16], 20 wild-type female flies were homogenized in 100 µl of 100 mM PIPES buffer (Sigma) with porcine kidney trehalase at 5 µl per 2 ml (Sigma) for 1 min at 10,000 rpm using a glass bead homogenizer. Trehalase converts trehalose (present in the hemolymph) into glucose, and thus total available glucose levels are measured. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In an experimental model of obesity and hyperglycemia in Drosophila melanogaster we studied the effect of diet modification and administration of metformin on systemic infection with Rhizopus, a common cause of mucormycosis in diabetic patients. Female Wt-type Drosophila flies were fed regular (RF) or high-fat diet (HFD; 30% coconut oil) food with or without metformin for 48 h and then injected with R. oryzae. Survival rates, glucose and triglyceride levels were compared between 1) normal-weight flies (RF), 2) obese flies (HFD), 3) obese flies fed with RF, 4) flies continuously on HFD + metformin, 5) flies fed on HFD + metformin, then transferred to RF, and 6) obese flies administered metformin after infection. Glucose levels were compared across groups of non-infected flies and across groups of infected flies. Survival was significantly decreased (P = 0.003) in obese flies, while post-infection glucose levels were significantly increased (P = 0.0001), compared to normal-weight flies. Diet and administration of metformin led to weight loss, normalized glucose levels during infection, and were associated with decreased mortality and tissue fungal burden. In conclusion, diet and metformin help control infection-associated hyperglycemia and improve survival in Drosophila flies with mucormycosis. Fly models of obesity bear intriguing similarities to the pathophysiology of insulin resistance and diabetes in humans, and can provide new insights into the pathogenesis and treatment of infections in obese and diabetic patients.
    Full-text · Article · Sep 2014 · PLoS ONE
Show more