Regulation of brain insulin mRNA by glucose and glucagon-like peptide 1.
Whether the brain synthesizes insulin is currently debated. Two clonal, immortalized mouse hypothalamic cell lines from e17, mHypoE-39 and mHypoE-46, express insulin 2 (Ins2), but not Ins1. We analyzed regions necessary for basal gene activity and found that the mouse Ins2 region -110/+183 bp stimulates promoter activity in hypothalamic neurons. The rat Ins2 showed moderate activity, whereas the human promoter construct is repressed below basal levels. In MIN6 pancreatic beta-cells, all of the Ins1 and Ins2 promoter constructs display high levels of transcriptional activity. The cell lines also express components of glucose-sensing machinery and the endogenous glucagon-like peptide 1 receptor (Glp-1R). We observed that 16.7 mM glucose induces Ins2 mRNA, while forskolin and a Glp-1 agonist, exendin-4, induce a biphasic Ins2 mRNA response in mHypoE-39 neurons. The insulin cis-regulatory regions differ between the pancreas and the hypothalamus, and glucose and Glp-1 regulate the expression of hypothalamic insulin.
Madadi
Golnaz
G
Department of Physiology, University of Toronto, Medical Science Building 3247 A, King's College Circle, Toronto, Ont., Canada M5S 1A8.
Dalvi
Prasad S
PS
Belsham
Denise D
DD
D000818:Animals; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000077270:Exenatide; D015870:Gene Expression; D052216:Glucagon-Like Peptide 1 / Q000819:agonists / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000096:biosynthesis*; D050417:Insulin-Secreting Cells / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D010455:Peptides / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D014688:Venoms / Q000494:pharmacology
D007328:Insulin; D010455:Peptides; D012333:RNA, Messenger; D014688:Venoms; D005576:Colforsin; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D005947:Glucose