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

ABSTRACT: 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.

SUBMITTER: Subramanian M

PROVIDER: S-EPMC3634656 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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

Subramanian Manivannan M Metya Suman Kumar SK Sadaf Sufia S Kumar Satish S Schwudke Dominik D Hasan Gaiti G

Disease models & mechanisms 20130208 3

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 ...[more]

PMID: 23471909

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Project description:BackgroundSec8 is highly expressed in mammalian nervous systems and has been proposed to play a role in several aspects of neural development and function, including neurite outgrowth, calcium-dependent neurotransmitter secretion, trafficking of ionotropic glutamate receptors and regulation of neuronal microtubule assembly. However, these models have never been tested in vivo. Nervous system development and function have not been described after mutation of sec8 in any organism.ResultsWe identified lethal sec8 mutants in an unbiased forward genetic screen for mutations causing defects in development of glutamatergic Drosophila neuromuscular junctions (NMJs). The Drosophila NMJ is genetically malleable and accessible throughout development to electrophysiology and immunocytochemistry, making it ideal for examination of the sec8 mutant synaptic phenotype. We developed antibodies to Drosophila Sec8 and showed that Sec8 is abundant at the NMJ. In our sec8 null mutants, in which the sec8 gene is specifically deleted, Sec8 immunoreactivity at the NMJ is eliminated but immunoblots reveal substantial maternal contribution in the rest of the animal. Contrary to the hypothesis that Sec8 is required for neurite outgrowth or synaptic terminal growth, immunocytochemical examination revealed that sec8 mutant NMJs developed more branches and presynaptic terminals during larval development, compared to controls. Synaptic electrophysiology showed no evidence that Sec8 is required for basal neurotransmission, though glutamate receptor trafficking was mildly disrupted in sec8 mutants. The most dramatic NMJ phenotype in sec8 mutants was an increase in synaptic microtubule density, which was approximately doubled compared to controls.ConclusionSec8 is abundant in the Drosophila NMJ. Sec8 is required in vivo for regulation of synaptic microtubule formation, and (probably secondarily) regulation of synaptic growth and glutamate receptor trafficking. We did not find any evidence that Sec8 is required for basal neurotransmission.

Dataset Information

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

Publications

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

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