Altered lipid homeostasis in Drosophila InsP3 receptor mutants leads to obesity and hyperphagia

National Centre for Biological Sciences, TIFR, Bangalore, India.
Disease Models and Mechanisms (Impact Factor: 4.97). 02/2013; 6(3). DOI: 10.1242/dmm.010017
Source: PubMed


Obesity is a complex metabolic disorder that often manifests with a strong genetic component in humans. However, the genetic basis for obesity and the accompanying metabolic syndrome is poorly defined. At a metabolic level obesity arises from an imbalance between nutritional intake and energy utilization of an organism. Mechanisms that sense the metabolic state of the individual and convey this information to satiety centers, help achieve this balance. Mutations in genes that alter or modify such signaling mechanisms are likely to lead to either obese individuals, who in mammals are at high risk for diabetes and cardiovascular disease, or excessively thin individuals with accompanying health problems. Here we show that Drosophila mutants for an intracellular calcium signaling channel, the inositol 1,4,5-trisphosphate receptor (InsP3R) store excess triglycerides in their fat bodies and become unnaturally obese on a normal diet. While excess insulin signaling can rescue obesity in InsP3R mutants to an extent, we show that it is not the only cause of the defect. Rather, through mass spectrometric analysis of lipid profiles we find that homeostasis of storage and membrane lipids are altered in InsP3R mutants. Possibly as a compensatory mechanism, InsP3R mutant adults also feed excessively. Thus reduced InsP3R function alters lipid metabolism and causes hyperphagia in adults. Together the metabolic and behavioral change leads to obesity. Our results implicate altered InsP3 signaling as a novel causative factor for metabolic syndrome in humans. Importantly our studies also suggest preventive dietary interventions.

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Available from: Dominik Schwudke, Sep 12, 2014
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    • "The ER calcium sensor STIM1 was found to negatively regulate the differentiation of 3T3-L1 preadipocytes (Graham et al., 2009). Drosophila IP 3 R mutants exhibit excessive food intake and obesity (Subramanian et al., 2013). "
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    ABSTRACT: Adipose tissue is central to the regulation of lipid metabolism. Berardinelli-Seip congenital lipodystrophy type 2 (BSCL2), one of the most severe lipodystrophy diseases, is caused by mutation of the Seipin gene. Seipin plays an important role in adipocyte differentiation and lipid homeostasis, but its exact molecular functions are still unknown. Here, we show that Seipin physically interacts with the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA) in both Drosophila and man. SERCA, an endoplasmic reticulum (ER) calcium pump, is solely responsible for transporting cytosolic calcium into the ER lumen. Like dSeipin, dSERCA cell-autonomously promotes lipid storage in Drosophila fat cells. dSeipin affects dSERCA activity and modulates intracellular calcium homeostasis. Adipose tissue-specific knockdown of the ER-to-cytosol calcium release channel ryanodine receptor (RyR) partially restores fat storage in dSeipin mutants. Our results reveal that Seipin promotes adipose tissue fat storage by regulating intracellular calcium homeostasis.
    Cell metabolism 05/2014; 19(5):861-71. DOI:10.1016/j.cmet.2014.03.028 · 17.57 Impact Factor
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    • "However, little is known about the identity of the genes which relay Akh/AkhR signalling to iCa 2þ increase in fat body cells in the context of storage lipid mobilization. We and others have recently shown a reverse correlation between the iCa 2þ in fat body cells and the body fat content in adult flies (Subramanian et al., 2013; Baumbach et al., 2014). Obese flies resulted from the functional impairment of any of the core component of the so-called store-operated calcium entry (SOCE). "
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    ABSTRACT: Adaptive mobilization of body fat is essential for energy homeostasis in animals. In insects, the adipokinetic hormone (AKH) systemically controls body fat mobilization. Biochemical evidence supports that AKH signals via a G protein-coupled receptor (GPCR) called AKH receptor (AKHR) using cyclic-AMP (cAMP) and Ca2+ second messengers to induce storage lipid release from fat body cells. Recently, we provided genetic evidence that the intracellular calcium (iCa2+) level in fat storage cells controls adiposity in the fruit fly Drosophila melanogaster. However, little is known about the genes, which mediate AKH signalling downstream of the AKHR to regulate changes in iCa2+. Here, we used thermogenetics to provide in vivo evidence that the GPCR signal transducers G protein α q subunit (Gαq), G protein γ1 (Gγ1) and Phospholipase C at 21C (Plc21C) control cellular and organismal fat storage in Drosophila. Transgenic modulation of Gαq, Gγ1 and Plc21C affected the iCa2+ of fat body cells and the expression profile of the lipid metabolism effector genes midway and brummer, which results in severely obese or lean flies. Moreover, functional impairment of Gαq, Gγ1 and Plc21C antagonised AKH-induced fat depletion. This study characterized Gαq, Gγ1 and Plc21C as anti-obesity genes and supported the model that AKH employs the Gαq/Gγ1/Plc21C module of iCa2+ control to regulate lipid mobilization in adult Drosophila.
    Journal of Genetics and Genomics 05/2014; 41(5). DOI:10.1016/j.jgg.2014.03.005 · 3.59 Impact Factor
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    • "Oil red O staining demonstrated elevated TAGs in the guts of flies with IP3R knockdown indicating greater ingestion and digestion of lipids (Figure 4C). Next we tested if expression of itpr + in peptidergic neurons rescued the excess feeding observed in itpr ku [9]. itpr+ expression in peptidergic neurons of itpr ku rescued hyperphagia as evident from the significantly reduced level of red dye in the abdomens of rescued animals compared with control animals (Figure 5A, B). "
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    ABSTRACT: Intracellular calcium signaling regulates a variety of cellular and physiological processes. The inositol 1,4,5 trisphosphate receptor (IP3R) is a ligand gated calcium channel present on the membranes of endoplasmic reticular stores. In previous work we have shown that Drosophila mutants for the IP3R (itprku) become unnaturally obese as adults with excessive storage of lipids on a normal diet. While the phenotype manifests in cells of the fat body, genetic studies suggest dysregulation of a neurohormonal axis. We show that knockdown of the IP3R, either in all neurons or in peptidergic neurons alone, mimics known itpr mutant phenotypes. The peptidergic neuron domain includes, but is not restricted to, the medial neurosecretory cells as well as the stomatogastric nervous system. Conversely, expression of an itpr+ cDNA in the same set of peptidergic neurons rescues metabolic defects of itprku mutants. Transcript levels of a gene encoding a gastric lipase CG5932 (magro), which is known to regulate triacylglyceride storage, can be regulated by itpr knockdown and over-expression in peptidergic neurons. Thus, the focus of observed itpr mutant phenotypes of starvation resistance, increased body weight, elevated lipid storage and hyperphagia derive primarily from peptidergic neurons. The present study shows that itpr function in peptidergic neurons is not only necessary but also sufficient for maintaining normal lipid metabolism in Drosophila. Our results suggest that intracellular calcium signaling in peptidergic neurons affects lipid metabolism by both cell autonomous and non-autonomous mechanisms.
    BMC Neuroscience 12/2013; 14(1):157. DOI:10.1186/1471-2202-14-157 · 2.67 Impact Factor
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