The physiological function of the agouti-related peptide gene: the control of weight and metabolic rate.
The central melanocortin system plays an important role in the regulation of energy homeostasis both in rodents and humans, and melanocortin receptors appear to be the core of this system. Alpha-melanocyte-stimulating hormone (alpha-MSH) inhibits feeding through melanocrtin 3 and 4 receptors (MC3-R and MC4-R) as an endogenous agonist. Although mutations in the agouti gene cause an over-expression of agouti peptide which antagonizes effects of alpha-MSH at MC4-R in the brain and causes obese phenotypes, there was no evidence for the presence of an endogenous antagonist for MC3-R and MC4-R until agouti related protein (AGRP) was identified. AGRP is expressed primarily in the hypothalamic arcuate nucleus and central administration of AGRP stimulates feeding and weight gain, and decreases metabolic rate. Although a complete deletion of the AGRP gene does not produce any significant metabolic phenotypes, reduction in AGRP expression by RNA interference is associated with increased metabolic rate along with reduced weight gain. The currently available data suggest that elevated AGRP mRNA along with reduced proopiomelanocortin (POMC) mRNA is associated with many types of obesity and agents antagonizing the effect of AGRP may be a potential therapeutic target in treating obesity and obesity-associated disorders in which endogenous hypothalamic AGRP is elevated.
Fishberg Center for Neurobiology, Neurobiology of Aging Laboratories, Department of Geriatrics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Tooru M
TM
Mizuno
Hideo
H
Makimura
Charles V
CV
Mobbs
D054369:Agouti-Related Protein; D004734:Energy Metabolism / Q000502:physiology*; D005215:Fasting / Q000502:physiology; D005786:Gene Expression Regulation; D006801:Humans; D007031:Hypothalamus / Q000502:physiology*; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides / Q000235:genetics*; D009765:Obesity / Q000378:metabolism; D011506:Proteins / Q000235:genetics*; D012333:RNA, Messenger / Q000378:metabolism; D011956:Receptors, Cell Surface
C515198:AGRP protein, human; D054369:Agouti-Related Protein; D036341:Intercellular Signaling Peptides and Proteins; D009479:Neuropeptides; D011506:Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface