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

Subramanian, M. ; Metya, S. K. ; Sadaf, S. ; Kumar, S. ; Schwudke, D. ; Hasan, G. (2013) Altered lipid homeostasis in Drosophila InsP3 receptor mutants leads to obesity and hyperphagia Disease Models & Mechanisms, 6 (3). pp. 734-744. ISSN 1754-8403

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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 the 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. Although excess insulin signaling can rescue obesity in InsP3R mutants to some extent, we show that it is not the only cause of the defect. Through mass spectrometric analysis of lipids 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 changes lead to obesity. Our results implicate altered InsP3 signaling as a previously unknown causative factor for metabolic syndrome in humans. Importantly, our studies also suggest preventive dietary interventions.

Item Type:Article
Source:Copyright of this article belongs to The Company of Biologists.
ID Code:97918
Deposited On:16 Jan 2014 11:59
Last Modified:19 May 2016 09:59

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