Control of Lipid Metabolism by Tachykinin in Drosophila

Song, Wei; Veenstra, Jan A.; Perrimon, Norbert

doi:10.1016/j.celrep.2014.08.060

Cited by 182 publications

(208 citation statements)

References 39 publications

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“…Myo1A -Gal4 is specifically expressed in enterocytes 52 . In order to constitutively express NT in gut EE cells, a gut EE cell-specific TK promoter (2.0kb) 28,29 was cloned into attB-UAST lacking Gal4 binding sites followed by insertion of full-length NT cDNA and the resulting plasmid (TK-NT) was used to generate a transgenic line by insertion at the VK5 attP locus. To express NT in EE cells and knock down CG9918 by RNAi in EC cells, the following genotype was used: yw; Myo1A-Gal4/CG9918RNAi 27539 ; TK-NT / +.…”

Section: Methodsmentioning

confidence: 99%

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

Song

Zaytseva

et al. 2016

Nature

227

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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Section: Methodsmentioning

confidence: 99%

“…8d). Knockdown of CG9918 expression in ECs using Myo1A -Gal4 to drive UAS-CG9918 RNAi (TRiP 27539) expression in flies also expressing NT driven by the EE cell-specific tachykinin (TK) promoter 28,29 markedly attenuated NT-induced lipid droplet accumulation (Extended Data Fig. 8c).…”

mentioning

confidence: 99%

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

Song

Zaytseva

et al. 2016

Nature

227

237

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“…For tachykinins, it has been possible to produce a transgenic line that expresses exclusively in tachykinin-expressing EEs. Elimination of tachykinin in the gut led to an increase of lipid produced from glucose absorbed by the gut resulting in increased lipid storage by the fat body [47 ].…”

Section: Functions Of Insect Epsmentioning

confidence: 99%

Chemical identity, function and regulation of enteroendocrine peptides in insects

Wegener

Veenstra

2015

Current Opinion in Insect Science

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“…Lipids from third instar larval fat bodies were extracted and submitted for spectrophotometric analysis at the Beth Israel Deaconess Medical Center (BIDMC) Mass Spectrometry Facility (www.bidmcmassspec.org). TG measurement was performed as described (35,36). See SI Experimental Procedures for more details.…”

Section: Methodsmentioning

confidence: 99%

Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

Song

Owusu-Ansah

et al. 2017

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

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Mitochondrial dysfunction has been associated with obesity and metabolic disorders. However, whether mitochondrial perturbation in a single tissue influences mitochondrial function and metabolic status of another distal tissue remains largely unknown. We analyzed the nonautonomous role of muscular mitochondrial dysfunction in Drosophila. Surprisingly, impaired muscle mitochondrial function via complex I perturbation results in simultaneous mitochondrial dysfunction in the fat body (the fly adipose tissue) and subsequent triglyceride accumulation, the major characteristic of obesity. RNA-sequencing (RNA-seq) analysis, in the context of muscle mitochondrial dysfunction, revealed that target genes of the TGF-β signaling pathway were induced in the fat body. Strikingly, expression of the TGF-β family ligand, Activin-β (Actβ), was dramatically increased in the muscles by NF-κB/Relish (Rel) signaling in response to mitochondrial perturbation, and decreasing Actβ expression in mitochondrial-perturbed muscles rescued both the fat body mitochondrial dysfunction and obesity phenotypes. Thus, perturbation of muscle mitochondrial activity regulates mitochondrial function in the fat body nonautonomously via modulation of Activin signaling.mitochondrial synchrony | Activin-β | complex I perturbation | NF-κB/Relish | lipid metabolism I ndividual organs in a multicellular organism, besides performing their respective roles, must communicate with other organs to maintain systemic homeostasis. The central nervous system (CNS) in particular integrates information regarding the status of peripheral metabolic processes via hormonal signaling and directs energy homeostasis and feeding behavior (1). In addition, metabolic changes in a peripheral organ can affect the physiology of other peripheral organs (2, 3). The skeletal muscle system, which is newly recognized as playing endocrine-related roles, produces myokines after exercise to target other metabolic organs (liver, adipose tissue, pancreas, gut, and bone) and modulates systemic energy homeostasis (4).Mitochondria are semiautonomous organelles that integrate multiple physiological signals. Growing evidence indicates that mitochondrial alterations in one organ leads to abnormalities in biological processes in distal organs through hormonal signaling (5, 6). In addition to exercise, which induces mitochondrial activity and improves muscle performance, mitochondrial perturbationassociated muscle injury is also sufficient to modulate functions of other organs and change systemic outcomes via myokine production. For example, in mammals, mitochondrial dysfunction due to disruption of autophagic function in skeletal muscles results in elevated production of muscular FGF21 that triggers browning of white adipose tissue and increases lipid mobilization (7). Further, in Drosophila, mild mitochondrial distress in adult muscles delays aging via an increase of muscular ImpL2 production and remote suppression of insulin signaling in the fat body and brain (8). Despite these examples, molecula...

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Control of Lipid Metabolism by Tachykinin in Drosophila

Cited by 182 publications

References 39 publications

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

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

Chemical identity, function and regulation of enteroendocrine peptides in insects

Activin signaling mediates muscle-to-adipose communication in a mitochondria dysfunction-associated obesity model

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