Abstracts Category : Other

Regulation of Drosophila melanogaster body fat storage by store-operated calcium entry

by Yanjun Xu

The worldwide prevalence of obesity and related chronic diseases is a major health problem. Obesity is driven by energy imbalance in obesogenic environments, diets and lifestyles. The underlying mechanisms of energy imbalance involve complex interactions among multilayered regulatory networks in biological system, most components of which are conserved from fruit fly to human. Recently, calcium signaling has been identified as a central regulator of energy homeostasis, which integrates the cellular metabolic information in a variety of organs including adipose tissue, liver, and the brain. A link between acute modulation of calcium signaling in fat storage tissue and energy homeostasis has been investigated in previous research by interfering with the activity of a key calcium signaling component encoded by the gene Stromal interaction molecule (Stim), which regulates the store-operated calcium entry (SOCE). But how chronically impairing calcium signaling in fat storage tissue drives obesity remained to be elucidated. Here I present experimental evidence that G proteins G1, Gq49B, and phospholipase C at least partially mediate the activity of the adipokinetic hormone Akh/ adipokinetic hormone receptor (AkhR) signaling (functionally similar to mammalian glucagon), which mobilize the fat storage via the Stim-mediated SOCE. Using molecular genetics, transcriptome analysis, imaging, biochemical, as well as physiological and behavioral methods, I found that Stim-Transiently Induced (TI) RNAi transgene expression in the adult fat storage tissue of the fly causes a long-term impairment of STIM function and accumulation of body fat. This Long-term Impairment of STIM function induced Obesity (LISO) is primarily caused by an increased food intake of the flies, aggravated by reduced metabolic rate and locomotor activity. At the molecular level, Stim-TI in fat storage tissue of the fly caused increased lipid biosynthesis, reduced the expression of genes involved in lipolysis and fatty acid -oxidation. At the cellular and organ level, Stim-TI induced hyperphagia via an increased secretion of Akh from the neuroendocrine corpora cardiaca cells. The results also suggest that LISO flies develop Akh and insulin signaling resistance specifically in Drosophila adipose tissue. Taken together, the long-term impairment with Stim function that results from Stim-TI has dramatic consequences for the regulatory network that controls energy homeostasis. LISO provides a powerful and straightforward model for the study on the complex interactions of regulatory networks underlying obesity and its related diseases.Advisors/Committee Members: Khnlein, Ronald P. (advisor), Khnlein, Ronald P. (referee), Mansouri, Ahmed (referee).