Acute intracerebroventricular administration of either carboxyl-terminal or amino-terminal fragments of agouti-related peptide produces a long-term decrease in energy expenditure in rats.
We investigated if agouti-related peptide (AgRP), an endogenous antagonist of melanocortin receptors (MC3-R and MC4-R), effects energy expenditure in rats. Fragments of the carboxyl-terminal, AgRP (83-132), and the amino-terminals, AgRP (25-51) and AgRP (54-82), were administered intracerebroventricularly (ICV). Food intake, body weight and fat weight changes were measured 5 and/or 24 h after a single ICV injection of the fragments. Oxygen consumption and colonic temperature were measured as indices of energy expenditure, during 3 and 24 h after the ICV injections, respectively. An oral glucose tolerance test was performed 24 h after ICV AgRP (83-132) injection. Binding experiments were performed in HEK-293 cells that over-expressed human MC4-R. AgRP (83-132), but not AgRP (25-51) nor AgRP (54-82), induced a potent and long-lasting increase in the cumulative food intake. Both the carboxyl-terminal and amino-terminal AgRP fragments significantly decreased oxygen consumption and colonic temperature. Despite the absence of hyperphagia and cross-reactivities with MC4-R, AgRP (25-51) and AgRP (54-82) significantly increased body weight and epididymal/mesenteric fat weight. AgRP (83-132) did not affect glucose and insulin responses to the oral glucose tolerance test. AgRP causes a potent and long-lasting decrease in energy expenditure; an effect that is exhibited by carboxyl-terminal fragments and amino-terminal fragments that lack antagonist activity at the MC receptors. This suggests that the amino-terminal region of AgRP plays a regulatory role in energy metabolism.
Goto
Kyoko
K
Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe 6500017, Japan.
Inui
Akio
A
Takimoto
Yoshiyuki
Y
Yuzuriha
Hideki
H
Asakawa
Akihiro
A
Kawamura
Yoshihiro
Y
Tsuji
Hiroki
H
Takahara
Yukio
Y
Takeyama
Chie
C
Katsuura
Goro
G
Kasuga
Masato
M
D054369:Agouti-Related Protein; D000818:Animals; D004734:Energy Metabolism / Q000502:physiology*; D005951:Glucose Tolerance Test; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D009478:Neuropeptide Y / Q000008:administration & dosage / Q000378:metabolism; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D054369:Agouti-Related Protein; D009478:Neuropeptide Y; D010446:Peptide Fragments; C411703:agouti-related protein-(83-132)