Drosophila Adiponectin Receptor in Insulin Producing Cells Regulates Glucose and Lipid Metabolism by Controlling Insulin Secretion

et al. (2013) Drosophila Adiponectin Receptor in Insulin Producing Cells Regulates Glucose and Lipid Metabolism by Controlling Insulin Secretion. PLoS ONE 8(7): e68641. doi:10.1371/journal.pone.0068641 Drosophila Adiponectin Receptor in Insulin Producing Cells Regulates Glucose and Lipid Metabolism by Controlling Insulin Secretion Su-Jin Kwak 0 Seung-Hyun Hong 0 Rijan Bajracharya 0 Se-Yeol Yang 0 Kyu-Sun Lee 0 Kweon Yu 0 Andrew Wolfe, John Hopkins University School of Medicine, United States of America 0 1 Neurophysiology Research Group, Bionano Centre, Korea Research Institute of Bioscience and Biotechnology (KRIBB) , Daejeon , Korea , 2 Department of Functional Genomics, University of Science and Technology (UST) , Daejeon , Korea Adipokines secreted from adipose tissue are key regulators of metabolism in animals. Adiponectin, one of the adipokines, modulates pancreatic beta cell function to maintain energy homeostasis. Recently, significant conservation between Drosophila melanogaster and mammalian metabolism has been discovered. Drosophila insulin like peptides (Dilps) regulate energy metabolism similarly to mammalian insulin. However, in Drosophila, the regulatory mechanism of insulin producing cells (IPCs) by adipokine signaling is largely unknown. Here, we describe the discovery of the Drosophila adiponectin receptor and its function in IPCs. Drosophila adiponectin receptor (dAdipoR) has high homology with the human adiponectin receptor 1. The dAdipoR antibody staining revealed that dAdipoR was expressed in IPCs of larval and adult brains. IPC- specific dAdipoR inhibition (Dilp2.dAdipoR-Ri) showed the increased sugar level in the hemolymph and the elevated triglyceride level in whole body. Dilps mRNA levels in the Dilp2.dAdipoR-Ri flies were similar with those of controls. However, in the Dilp2.dAdipoR-Ri flies, Dilp2 protein was accumulated in IPCs, the level of circulating Dilp2 was decreased, and insulin signaling was reduced in the fat body. In ex vivo fly brain culture with the human adiponectin, Dilp2 was secreted from IPCs. These results indicate that adiponectin receptor in insulin producing cells regulates insulin secretion and controls glucose and lipid metabolism in Drosophila melanogaster. This study demonstrates a new adipokine signaling in Drosophila and provides insights for the mammalian adiponectin receptor function in pancreatic beta cells, which could be useful for therapeutic application. - Mammalian adipokines are produced and secreted from adipose tissue. They play a key role in maintaining energy homeostasis through inter-organ communications. Adiponectin, one of the adipokines, has multiple beneficial roles for regulating energy homeostasis, inflammation, and apoptosis [1,2]. Two adiponectin receptors, AdipoR1 and AdipoR2, are seven transmembrane domain proteins with inverted topology compared to G-protein coupled receptors [3]. AdipoR1 has a higher binding affinity to the globular form of adiponectin whereas AdipoR2 has a higher binding affinity to the full length adiponectin [3]. AdipoR1 and 2 double knockout mice increase the triglyceride level in the liver and exhibit insulin resistance and glucose intolerance, demonstrating that AdipoR1 and 2 regulate lipid and glucose homeostasis [2,4]. In the skeletal muscle and liver, adiponectin receptors activate AMPK (AMP-activated protein kinase), PPARalpha, and p38 MAPK to increase the insulin sensitivity [3]. An adaptor protein APPL1 binds to adiponectin receptors, which activates AMPK and p38 MAPK in the skeletal muscle [5]. However, the mechanism of how adiponectin receptors activate downstream effectors is not made clear and the adiponectin receptor signaling identified in the skeletal muscle is not always applicable in other tissues. A recent study showed that adiponectin receptors are associated with ceramidase activity and regulate cell apoptosis by adjusting the balance between ceramide and sphingosine-1 phosphate levels [6]. Although AdipoR1 and 2 are expressed in pancreatic beta cells [7,8], the function of adiponectin and AdipoRs in IPCs is less studied than in insulin target tissues such as liver and skeletal muscle [1,2]. Adiponectin knockout mice show impaired insulin secretion and intravenous injection of adiponectin to C57BL/6 mice induces insulin secretion [9,10]. These studies indicate that adiponectin regulates insulin secretion but IPC-specific modulation of AdipoR in the animal model has not been demonstrated to show that adiponectin directly regulates insulin secretion through AdipoR. During the last decade, significant conservation and parallelism were discovered between Drosophila and the mammalian metabolism. For example, Drosophila insulin like peptides (Dilps) regulate growth, energy metabolism, stress response, aging, and reproduction functions similar to that of mammalian Insulin/IGF signaling. Ablation of IPCs or deletion of Dilp genes results in decreased body size, retarded growth, and diabeti (...truncated)