The positive effects of growth hormone-releasing peptide-6 on weight gain and fat mass accrual depend on the insulin/glucose status.
Ghrelin and GH secretagogues, including GH-releasing peptide (GHRP)-6, stimulate food intake and adiposity. Because insulin modulates the hypothalamic response to GH secretagogues and acts synergistically with ghrelin on lipogenesis in vitro, we analyzed whether insulin plays a role in the metabolic effects of GHRP-6 in vivo. Streptozotocin-induced diabetic rats received saline, GHRP-6, insulin, or insulin plus GHRP-6 once daily for 8 wk. Rats receiving saline suffered hyperglycemia, hyperphagia, polydipsia, and weight loss. Insulin, but not GHRP-6, improved these parameters (P < 0.001 for all), as well as the diabetes-induced increase in hypothalamic mRNA levels of neuropeptide Y and agouti-related peptide and decrease in proopiomelanocortin. Cocaine amphetamine-related transcript mRNA levels were also reduced in diabetic rats, with GHRP-6 inducing a further decrease (P < 0.03) and insulin an increase. Diabetic rats receiving insulin plus GHRP-6 gained more weight and had increased epididymal fat mass and serum leptin levels compared with all other groups (P < 0.001). In epididymal adipose tissue, diabetic rats injected with saline had smaller adipocytes (P < 0.001), decreased fatty acid synthase (FAS; P < 0.001), and glucose transporter-4 (P < 0.001) and increased hormone sensitive lipase (P < 0.001) and proliferator-activated receptor-gamma mRNA levels (P < 0.01). Insulin normalized these parameters to control values. GHRP-6 treatment increased FAS and glucose transporter-4 gene expression and potentiated insulin's effect on epididymal fat mass, adipocyte size (P < 0.001), FAS (P < 0.001), and glucose transporter-4 (P < 0.05). In conclusion, GHRP-6 and insulin exert an additive effect on weight gain and visceral fat mass accrual in diabetic rats, indicating that some of GHRP-6's metabolic effects depend on the insulin/glucose status.
Granado
Miriam
M
Department of Endocrinology, Hospital Infantil Universitario Niño Jesús, Avenida Menéndez Pelayo, Madrid, Spain.
García-Cáceres
Cristina
C
Frago
Laura M
LM
Argente
Jesús
J
Chowen
Julie A
JA
D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism; D054369:Agouti-Related Protein / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D002096:C-Peptide / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000503:physiopathology; D004822:Epididymis / Q000187:drug effects / Q000378:metabolism; D005223:Fats / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D054439:Ghrelin / Q000097:blood; D051275:Glucose Transporter Type 4 / Q000235:genetics; D013006:Growth Hormone / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000494:pharmacology*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D020738:Leptin / Q000097:blood; D008297:Male; D009478:Neuropeptide Y / Q000235:genetics; D009842:Oligopeptides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015430:Weight Gain / Q000187:drug effects*
D054369:Agouti-Related Protein; D001786:Blood Glucose; D002096:C-Peptide; D005223:Fats; D054439:Ghrelin; D051275:Glucose Transporter Type 4; D007328:Insulin; D020738:Leptin; D009478:Neuropeptide Y; D009842:Oligopeptides; C548904:insulin-like growth factor-1, rat; C041048:growth hormone releasing hexapeptide; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone; D064429:Fatty Acid Synthases