Melanin-concentrating hormone induces insulin resistance through a mechanism independent of body weight gain.
Transgenic hyperexpression of melanin-concentrating hormone (MCH) produces a phenotype of obesity and glucose intolerance. However, it is not known whether under this specific condition, glucose intolerance develops as a direct consequence of hyperexpressed MCH or is secondary to increased adiposity. Here, rats were treated i.c.v. with MCH or with an antisense oligonucleotide to MCH (MCH-ASO). MCH promoted an increase in blood glucose and a decrease in blood insulin levels during a glucose tolerance test. MCH also caused a decrease in the constant of glucose disappearance during an insulin tolerance test. All these effects of MCH were independent of body weight variation and were accompanied by reduced insulin receptor substrate (IRS)-1 engagement of phosphatidylinositol-3 kinase (PI3-kinase) in white and brown adipose tissues, skeletal muscle and liver and by reduced Akt activation in skeletal muscle. MCH also led to a significant reduction in ERK activation in white adipose tissue. Finally, inhibition of hypothalamic MCH expression promoted a significant increase in ERK activation in brown adipose tissue. We conclude that hypothalamic MCH controls glucose homeostasis through mechanisms that are, at least in part, independent of adiposity.
Pereira-da-Silva
Márcio
M
Department of Internal Medicine, State University of Campinas, SP, Brazil.
De Souza
Cláudio T
CT
Gasparetti
Alessandra L
AL
Saad
Mário J A
MJ
Velloso
Lício A
LA
D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D015870:Gene Expression; D005951:Glucose Tolerance Test; D007028:Hypothalamic Hormones / Q000235:genetics* / Q000494:pharmacology*; D007328:Insulin / Q000097:blood; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism; D008297:Male; D008543:Melanins / Q000235:genetics* / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010907:Pituitary Hormones / Q000235:genetics* / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D015430:Weight Gain
D001786:Blood Glucose; D007028:Hypothalamic Hormones; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008543:Melanins; D016376:Oligonucleotides, Antisense; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D010907:Pituitary Hormones; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C526296:Irs1 protein, rat; C019463:melanin-concentrating hormone; C494920:Akt1 protein, rat