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 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.
SourceAvailable from: Rubén Nogueiras[Show abstract] [Hide abstract]
ABSTRACT: Intracellular calcium-permeable channels have been implicated in thermogenic function of murine brown and brite/beige adipocytes, respectively transient receptor potential melastin-8 (TRPM8) and vanilloid-4 (TRPV4). Since the endo-lysosomal two-pore channels (TPCs) have also been ascribed with metabolic functionality, we studied the effect of simultaneously knocking out TPC1 and TPC2 on body composition and energy balance in male mice fed a chow diet. Compared with wild-type (WT) mice, TPC1 and TPC2 double knockout (Tpcn1/2(-/-)) animals had a higher respiratory quotient and became obese between 6 and 9 months of age. While food intake was unaltered, interscapular brown adipose tissue (BAT) maximal temperature and lean-mass adjusted oxygen consumption were lower in Tpcn1/2(-/-) than in WT. Phosphorylated hormone-sensitive lipase expression and lipid density, and expression of beta-adrenergic receptors were also lower in Tpcn1/2(-/-) BAT, while mitochondrial respiratory chain function and uncoupling protein-1 expression remained intact. We conclude that Tpcn1/2(-/-) mice show mature-onset obesity due to reduced lipid availability and utilisation, and a defect in beta-adrenergic receptor signaling, leading to impaired thermogenic activity, in BAT.Endocrinology 12/2014; 156(3):en20141766. DOI:10.1210/en.2014-1766 · 4.64 Impact Factor
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ABSTRACT: Animals respond to changes in food availability by adjusting sleep and foraging strategies to optimize their fitness. Wild populations of the fruit fly, Drosophila melanogaster, display highly variable levels of starvation resistance that are dependent on geographic location, food availability, and evolutionary history. How behaviors that include sleep and feeding vary in Drosophila with increased starvation resistance is unclear. We have generated starvation resistant flies through experimental evolution to investigate the relationship between foraging behaviors and starvation resistance. Outbred populations of D. melanogaster were selected for starvation resistance over 60 generations. This selection process resulted in flies with a three-fold increase in total lipids that survive up to 18 days without food. We tested starvation-selected (S) flies for sleep and feeding behaviors to determine the effect that selection for starvation resistance has had on foraging behavior. Flies from three replicated starvation-selected populations displayed a dramatic reduction in feeding and prolonged sleep duration compared to fed control (F) populations, suggesting that modified sleep and feeding may contribute to starvation resistance. A prolonged larval developmental period contributes to the elevated energy stores present in starvation-selected flies. By preventing S larvae from feeding longer than F larvae, we were able to reduce energy stores in adult S flies to levels seen in adult F flies, thus allowing us to control for energy storage levels. However, the reduction of energy stores in S flies fails to generate normal sleep and feeding behavior seen in F flies with similar energy stores. These findings suggest that the behavioral changes observed in S flies are due to genetic regulation of behavior rather than elevated lipid levels. Testing S-F hybrid individuals for both feeding and sleep revealed a lack of correlation between food consumption and sleep duration, indicating further independence in genetic factors underlying the sleep and feeding changes observed in S flies. Taken together, these findings provide evidence that starvation selection results in prolonged sleep and reduced feeding through a mechanism that is independent of elevated energy stores. These findings suggest changes in both metabolic function and behavior contribute to the increase in starvation resistance seen in flies selected for starvation resistance.Journal of Experimental Biology 06/2014; 217(17). DOI:10.1242/jeb.103309 · 3.00 Impact Factor
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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 · 16.75 Impact Factor