title: Central melanocortin receptor agonist reduces hepatic lipogenic gene expression in streptozotocin-induced diabetic mice.
abstract: OBJECTIVE
  The central melanocortin system regulates a variety of metabolic functions including lipid metabolism and hepatic lipogenic gene expression. The objective of the present study was to determine whether central melanocortin regulates hepatic lipogenic gene expression under insulin insufficient condition.
  
  
  METHODS
  We examined the effect of intracerebroventricular (i.c.v.) injection of MTII, a melanocortin agonist, on hepatic gene expression in a mouse model of the insulin-deficient diabetes. Diabetes was induced in male C57BL/6J mice by intraperitoneal injections of streptozotocin (STZ). Diabetic mice received daily i.c.v. injections of MTII (3 nmol) for 11 days. Hepatic expression levels of lipogenic genes and their transcription factors were measured.
  
  
  RESULTS
  MTII treatment significantly reduced hepatic expression levels of genes encoding lipid biosynthetic enzymes, stearoyl-CoA desaturase 1 (SCD1), glycerol-3-phosphate acyltransferase 1 (GPAT1), acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1), and DGAT2 mRNA without significant changes in serum insulin levels, homeostasis model-assessment of insulin resistance (HOMA-IR) and glucose tolerance in STZ-induced diabetic mice. MTII treatment also reduced fatty acid synthase (FAS) and SCD1 protein levels in the liver of diabetic mice. Expression levels of genes encoding transcription factors of these lipogenic genes, sterol regulatory element-binding protein 1c (SREBP-1c) and peroxisome proliferator-activated receptor γ2 (PPARγ2) were also significantly reduced by MTII treatment.
  
  
  CONCLUSIONS
  These data suggest that the insulin-independent mechanism is involved in the regulation of hepatic lipogenic gene expression. Enhanced central melanocortin signaling may be effective in improving abnormal lipid metabolism associated with insulin-deficiency or insulin-insufficiency.
authors.affiliation: Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada R3E 0J9.
authors.forename: Arnold
authors.initials: A
authors.lastname: Leckstrom
authors.forename: Pei San
authors.initials: PS
authors.lastname: Lew
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Poritsanos
authors.forename: Tooru M
authors.initials: TM
authors.lastname: Mizuno
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D007276:Injections, Intraventricular; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D044101:Receptors, Melanocortin / Q000819:agonists* / Q000378:metabolism; D013311:Streptozocin; D014157:Transcription Factors / Q000378:metabolism; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D007328:Insulin; D044101:Receptors, Melanocortin; D014157:Transcription Factors; C105974:acetyl-norleucyl(4)-(aspartyl(5)-histidyl(6)-phenylalanyl(7)-arginyl(8)-tryptophyl(9)-lysyl(10))cyclo-alpha-MSH(4-10)amide; D000521:alpha-MSH; D013311:Streptozocin