title: Negative regulation of hepatic fat mass and obesity associated (Fto) gene expression by insulin.
abstract: OBJECTIVE
  To investigate the role of glucose and insulin in the regulation of hepatic fat mass and obesity associated (Fto) gene expression and the role of hepatic Fto in the regulation of gluconeogenic gene expression.
  
  
  METHODS
  To determine the effect of hyperglycemia on hepatic Fto expression, levels of Fto mRNA in liver were compared between normoglycemic/normoinsulinemic, hypereglycemic/hyperinsulinemic, and hyperglycemic/hypoinsulinemic mice. To determine the direct effect of insulin on Fto expression, levels of Fto, glucose-6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (Pepck) mRNA levels were compared between control and insulin-treated mouse liver tissues cultured ex vivo and immortalized mouse hepatocytes AML12. To determine the role of Fto in the regulation of gluconeogenic gene expression, we examined the effect of enhanced Fto expression on G6pase and Pepck mRNA levels in AML12 cells.
  
  
  RESULTS
  Fto mRNA levels were significantly reduced in hyperglycemic/hyperinsulinemic mice compared to normoglycemic/normoinsulinemic mice, while they were indistinguishable between hyperglycemic/hypoinsulinemic mice and normoglycemic/normoinsulinemic mice. Insulin treatment reduced Fto, G6pase, and Pepck mRNA levels compared to control vehicle treatment in both ex vivo cultured mouse liver tissues and AML12 cells. Enhanced Fto expression significantly increased G6pase and Pepck mRNA level in AML12 cells.
  
  
  CONCLUSIONS
  Our findings support the hypothesis that hepatic Fto participates in the maintenance of glucose homeostasis possibly by mediating the inhibitory effect of glucose and insulin on gluconeogenic gene expression in liver. It is further suggested that impairments in nutritional and hormonal regulation of hepatic Fto expression may lead to impairments in glycemic control in diabetes.
authors.affiliation: Division of Endocrinology and Metabolic Diseases, Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada. Electronic address: Tooru.Mizuno@umanitoba.ca.
authors.forename: Tooru M
authors.initials: TM
authors.lastname: Mizuno
authors.affiliation: Division of Endocrinology and Metabolic Diseases, Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
authors.forename: Pei San
authors.initials: PS
authors.lastname: Lew
authors.affiliation: Division of Endocrinology and Metabolic Diseases, Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
authors.forename: Yanming
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Division of Endocrinology and Metabolic Diseases, Department of Physiology & Pathophysiology, University of Manitoba, Winnipeg, Manitoba R3E 0J9, Canada.
authors.forename: Arnold
authors.initials: A
authors.lastname: Leckstrom
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism*; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO / Q000378:metabolism*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005943:Gluconeogenesis; D005947:Glucose / Q000378:metabolism; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology; D006706:Homeostasis; D006943:Hyperglycemia / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D007328:Insulin; D012333:RNA, Messenger; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D005952:Glucose-6-Phosphatase; D019764:Phosphoenolpyruvate Carboxykinase (ATP); D005947:Glucose
keywords: Gluconeogenesis; Glycemic control; Hyperglycemia; Insulin; Liver