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

Birse, Ryan T.; Choi, Joan; Reardon, Kathryn; Rodriguez, Jessica; Graham, Suzanne; Diop, Soda Balla; Ocorr, Karen; Bodmer, Rolf; Oldham, Sean

doi:10.1016/j.cmet.2010.09.014

Cited by 332 publications

(511 citation statements)

References 60 publications

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“…We next tested whether flies with muscle-specific skd or kto knockdown were more susceptible to triglyceride accumulation on a high-fat diet, which contains coconut oil as the source of saturated fat (28). Newly eclosed flies with Mef2-Gal4-driven knockdown of skd or kto were fed normal food for 12 d and then moved to either fresh normal food or high-fat food containing 30% coconut oil.…”

Section: Resultsmentioning

confidence: 99%

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Lee

Bassel‐Duby

Olson

2014

Proc. Natl. Acad. Sci. U.S.A.

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Obesity develops in response to an imbalance of energy homeostasis and whole-body metabolism. Muscle plays a central role in the control of energy homeostasis through consumption of energy and signaling to adipose tissue. We reported previously that MED13, a subunit of the Mediator complex, acts in the heart to control obesity in mice. To further explore the generality and mechanistic basis of this observation, we investigated the potential influence of MED13 expression in heart and muscle on the susceptibility of Drosophila to obesity. Here, we show that heart/muscle-specific knockdown of MED13 or MED12, another Mediator subunit, increases susceptibility to obesity in adult flies. To identify possible muscle-secreted obesity regulators, we performed an RNAi-based genetic screen of 150 genes that encode secreted proteins and found that Wingless inhibition also caused obesity. Consistent with these findings, muscle-specific inhibition of Armadillo, the downstream transcriptional effector of the Wingless pathway, also evoked an obese phenotype in flies. Epistasis experiments further demonstrated that Wingless functions downstream of MED13 within a muscle-regulatory pathway. Together, these findings reveal an intertissue signaling system in which Wingless acts as an effector of MED13 in heart and muscle and suggest that Wingless-mediated cross-talk between striated muscle and adipose tissue controls obesity in Drosophila. This signaling system appears to represent an ancestral mechanism for the control of systemic energy homeostasis.O besity is a systemic disorder caused by an energy imbalance in which energy input exceeds energy utilization, resulting in accumulation of excess body fat. Muscle plays a central role in systemic energy homeostasis by consuming nutrients and signaling in an endocrine manner to other tissues (1-3). Thus, there has been intense interest in identifying secreted factors from muscle that modulate the function of adipose tissue.Previously, we reported that cardiac deletion of MED13, a subunit of the Mediator complex, increases susceptibility to obesity in mice whereas cardiac overexpression of MED13 confers a lean phenotype (4), revealing an unforeseen function of the heart as a systemic regulator of energy homeostasis. The Mediator is a conserved multisubunit complex that mediates the interaction between RNA polymerase II and transcription factors and therefore governs transcription in all eukaryotes (5). MED13 and MED12 are among four subunits of the auxiliary kinase module, which confers additional regulatory functions to the Mediator complex (6). Expression profiling of yeast mutants or gene-depleted Drosophila cell lines revealed a close correlation between the gene-expression programs controlled by MED13 and MED12, suggesting their concerted actions in gene regulation (7,8).Drosophila provides a powerful model system for the genetic analysis of obesity (9-11). The processes that regulate energy homeostasis, such as energy storage and mobilization of fat in adipose tissue of the fat bo...

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Section: Resultsmentioning

confidence: 99%

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Lee

Bassel‐Duby

Olson

2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Adult flies were fed HFD or standard fly food (cornmeal-yeast) as described 25 . Briefly, flies (5d after emerging) were collected and maintained on standard fly food for an additional 5d, split into two groups, and fed either standard fly food or standard fly food containing 20% (w/v) coconut oil for a further 5d, followed by dissection and lipid staining using Bodipy or Nile Red.…”

Section: Methodsmentioning

confidence: 99%

“…3c) of Gr36C -NT 3 rd instar larvae. Next, we used a diet-induced obesity model in Drosophila 25 to demonstrate increased lipid droplets in the midgut of control flies fed HFD compared with flies fed a standard diet. NT expression dramatically increased lipid accumulation in the midgut (Fig.…”

mentioning

confidence: 99%

An obligatory role for neurotensin in high-fat-diet-induced obesity

Song

Zaytseva

et al. 2016

Nature

219

237

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Obesity and its associated comorbidities (e.g., diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually1 and are among the most prevalent and challenging conditions confronting the medical profession2,3. Neurotensin (NT), a 13-amino acid peptide predominantly localized in specialized enteroendocrine (EE) cells of the small bowel4 and released by fat ingestion5, facilitates fatty acid (FA) translocation in rat intestine6, and stimulates growth of various cancers7; the effects of NT are mediated through three known NT receptors (NTR1, 2 and 3)8. Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality9; however, a role for NT as a causative factor in these diseases is unknown. Here, we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates FA absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3/sortilin. Consistent with the findings in mice, expression of NT in Drosophila midgut EE cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.

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“…De manière remarquable, des mouches alimentées avec un régime riche en lipides développent des phénotypes caractéristiques de l'obésité -niveaux élevés de triglycérides, altération de la voie de l'insuline et de l'homéostasie du glucose -qui sont similaires aux réponses que l'on observe chez les mammifères [29]. Chez la drosophile, les lipides s'accumulent aussi au niveau du coeur conduisant à une réduction de sa contractilité et à des défauts structuraux symptomatiques de la lipotoxicité cardiaque qui rappellent les cardiomyopathies associées au diabète.…”

Section: Cardiopathies Et Métabolismeunclassified

Pathologies et vieillissement cardiaque

Perrin

Röder

2016

Med Sci (Paris)

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

Cited by 332 publications

References 60 publications

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

Heart- and muscle-derived signaling system dependent on MED13 and Wingless controls obesity in Drosophila

An obligatory role for neurotensin in high-fat-diet-induced obesity

Pathologies et vieillissement cardiaque

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