title: LIM-homeodomain transcription factor Isl-1 mediates the effect of leptin on insulin secretion in mice.
abstract: In addition to the well known regulating effects of leptin on energy balance and glucose homeostasis through the central nervous system, circulating leptin has a direct effect on pancreatic islet and insulin secretion through its receptor (OBRb). The LIM-homeodomain transcription factor Isl-1 is expressed in all classes of pancreatic endocrine cells and is involved in regulating both islet development and insulin secretion. Both OBRb and Isl-1 mutations result in obesity-related diabetes. However, the interactions and physiological significance of leptin and Isl-1 in pancreatic islets remain to be established. Here, we show that most of leptin target cells in pancreatic islets and NIT beta cells express Isl-1. Both in vivo and in vitro results demonstrate that leptin suppresses Isl-1 expression and insulin secretion in islet in physiological and pathophysiological conditions, e.g. high fat diet. This effect of leptin on insulin secretion is lost in leptin receptor-defective db/db and Isl-1-inducible knock-out mice. We conclude that the action of leptin on insulin secretion is at least partly mediated by Isl-1. Another new finding of this study is that Isl-1 acts as a direct downstream target of leptin signaling molecule STAT3 to influence the effect of leptin on insulin secretion, whereas inversely, insulin has feedback regulating effects on Isl-1 expression through JAK-STAT3 pathway. These findings are crucial for understanding the mechanisms regulating insulin secretion and metabolism in related diseases, such as obesity and type 2 diabetes.
authors.affiliation: State Key Laboratory of Agrobiotechnology, College of Biological Sciences, China Agricultural University, Beijing 100193, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Chen
authors.forename: Rui
authors.initials: R
authors.lastname: Fu
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.forename: Yu-shan
authors.initials: YS
authors.lastname: Li
authors.forename: Ji-rong
authors.initials: JR
authors.lastname: Pan
authors.forename: Jia-li
authors.initials: JL
authors.lastname: Liu
authors.forename: Hao-shu
authors.initials: HS
authors.lastname: Luo
authors.forename: Jing-dong
authors.initials: JD
authors.lastname: Yin
authors.forename: De-fa
authors.initials: DF
authors.lastname: Li
authors.forename: Sheng
authors.initials: S
authors.lastname: Cui
mesh_terms: D000818:Animals; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D060850:LIM-Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D020738:Leptin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese; D009154:Mutation; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D054411:Receptors, Leptin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D007328:Insulin; D060850:LIM-Homeodomain Proteins; D020738:Leptin; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1