Intermittent MTII application evokes repeated anorexia and robust fat and weight loss.
Central melanocortins (MC) evoke potent but transient anorectic responses with tachyphylaxis developing within days. We hypothesized that intermittent therapy using the MC analog, melanotan II (MTII), would minimize the tachyphylaxis and enhance the long-term efficacy of MTII treatment. F344/BN rats were infused with MTII or vehicle into the lateral ventricle by mini pump for 14 days. Half the MTII-infused rats were then given vehicle (MTII-On/Off), while the remaining received fresh MTII (MTII-On) for 10 days. Finally, pumps in both groups were replaced with ones containing fresh MTII for an additional 6 days. The first MTII application induced a 30% food reduction that attenuated within 5 days. Reapplication of MTII in MTII-On/Off rats, after the off period, invoked a new and equally robust anorectic response while continuation of MTII supplement in the MTII-On group did not change food intake from the control level. Body weights decreased similarly in both MTII groups at termination (day 30). Hypothalamic MC3 receptor, AgRP, and POMC expressions were unchanged, but MC4 receptor expression was diminished by 25%, and adiposity reduced by 80% in both MTII groups. Acetyl-CoA carboxylase 1 phosphorylation was elevated in perirenal fat by over 10 fold with either MTII treatment. In conclusion, intermittent MTII treatment preserves anorectic responses but does not prevent tachyphylaxis, whereas constant MTII application blunts further food response after the initial tachyphylaxis. Either form of MTII administration results in significant weight and adiposity reductions, involving perhaps fatty acid oxidation within specific adipose tissues.
Zhang
Yi
Y
Research Department, Malcom Randall Veterans Affairs Medical Center-NF/SG HSC, Rm E585-1, 1601 SW Archer Road, Gainesville, FL 32608, USA. yizhang@ufl.edu
Collazo
Renata
R
Gao
Yongxin
Y
Li
Gang
G
Scarpace
Philip J
PJ
D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000273:Adipose Tissue / Q000187:drug effects*; D000818:Animals; D000855:Anorexia / Q000139:chemically induced*; D001835:Body Weight / Q000187:drug effects*; D006801:Humans; D007473:Ion Channels / Q000378:metabolism; D008297:Male; D024101:Mitochondrial Proteins / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D000071256:Uncoupling Protein 1; D015431:Weight Loss / Q000187:drug effects*; D000521:alpha-MSH / Q000031:analogs & derivatives* / Q000494:pharmacology
D007473:Ion Channels; D024101:Mitochondrial Proteins; D010456:Peptides, Cyclic; D000071256:Uncoupling Protein 1; C079282:melanotan-II; D000521:alpha-MSH; D000103:Acetyl-CoA Carboxylase