title: Insulin-stimulated leptin secretion requires calcium and PI3K/Akt activation.
abstract: Numerous studies have focused on the regulation of leptin signalling and the functions of leptin in energy homoeostasis; however, little is known about how leptin secretion is regulated. In the present study we studied leptin storage and secretion regulation in 3T3-L1 and primary adipocytes. Leptin is stored in membrane-bound vesicles that are localized predominantly in the ER (endoplasmic reticulum) and close to the plasma membrane of both 3T3-L1 and primary adipocytes. Insulin increases leptin secretion as early as 15 min without affecting the leptin mRNA level. Interestingly, treatment with the protein synthesis inhibitor cycloheximide and the ER-Golgi trafficking blocker Brefeldin A inhibit both basal and ISLS (insulin-stimulated leptin secretion), suggesting that insulin stimulates leptin secretion by up-regulating leptin synthesis and that leptin-containing vesicles go through the ER-Golgi route. The PI3K (phosphoinositide 3-kinase)/Akt, but not MAPK (mitogen-activated protein kinase), pathway is involved in ISLS in vitro and in vivo. Although Ca2+ triggers synaptic vesicle and secretory granule exocytosis, Ca2+ influx alone is not sufficient to induce leptin secretion. Remarkably, Ca2+ is required for ISLS possibly due to its involvement in insulin-stimulated Akt phosphorylation. We conclude that insulin stimulates leptin release through the PI3K/Akt pathway and that Ca2+ is required for robust Akt phosphorylation and leptin secretion.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: *Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), Singapore.
authors.forename: Yusuf
authors.initials: Y
authors.lastname: Ali
authors.forename: Chun-Yan
authors.initials: CY
authors.lastname: Lim
authors.forename: Wanjin
authors.initials: W
authors.lastname: Hong
authors.affiliation: §Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ, U.S.A.
authors.forename: Zhiping P
authors.initials: ZP
authors.lastname: Pang
authors.forename: Weiping
authors.initials: W
authors.lastname: Han
mesh_terms: D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004789:Enzyme Activation; D006056:Golgi Apparatus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D022142:Secretory Vesicles / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007328:Insulin; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D002118:Calcium