In vivo evidence for inverse agonism of Agouti-related peptide in the central nervous system of proopiomelanocortin-deficient mice.
OBJECTIVE
Melanocyte-stimulating hormone (MSH) peptides processed from proopiomelanocortin (POMC) regulate energy homeostasis by activating neuronal melanocortin receptor (MC-R) signaling. Agouti-related peptide (AgRP) is a naturally occurring MC-R antagonist but also displays inverse agonism at constitutively active melanocortin-4 receptor (MC4-R) expressed on transfected cells. We investigated whether AgRP functions similarly in vivo using mouse models that lack all neuronal MSH, thereby precluding competitive antagonism of MC-R by AgRP.


METHODS
Feeding and metabolic effects of the MC-R agonist melanotan II (MTII), AgRP, and ghrelin were investigated after intracerebroventricular injection in neural-specific POMC-deficient (Pomc(-/-)Tg/+) and global POMC-deficient (Pomc(-/-)) mice. Gene expression was quantified by RT-PCR.


RESULTS
Hyperphagic POMC-deficient mice were more sensitive than wild-type mice to the anorectic effects of MTII. Hypothalamic melanocortin-3 (MC3)/4-R mRNAs in POMC-deficient mice were unchanged, suggesting increased receptor sensitivity as a possible mechanism for the heightened anorexia. AgRP reversed MTII-induced anorexia in both mutant strains, demonstrating its ability to antagonize MSH agonists at central MC3/4-R, but did not produce an acute orexigenic response by itself. The action of ghrelin was attenuated in Pomc(-/-)Tg/+ mice, suggesting decreased sensitivity to additional orexigenic signals. However, AgRP induced delayed and long-lasting modifications of energy balance in Pomc(-/-)Tg/+, but not glucocorticoid-deficient Pomc(-/-) mice, by decreasing oxygen consumption, increasing the respiratory exchange ratio, and increasing food intake.


CONCLUSIONS
These data demonstrate that AgRP can modulate energy balance via a mechanism independent of MSH and MC3/4-R competitive antagonism, consistent with either inverse agonist activity at MC-R or interaction with a distinct receptor.
Tolle
Virginie
V
Center for the Study of Weight Regulation and Associated Disorders, Oregon Health and Science University, Portland, Oregon, USA. virginie.tolle@broca.inserm.fr
Low
Malcolm J
MJ
D054369:Agouti-Related Protein / Q000008:administration & dosage / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D000855:Anorexia / Q000503:physiopathology; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000502:physiology*; D017931:DNA Primers; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D054439:Ghrelin / Q000008:administration & dosage / Q000494:pharmacology*; D006963:Hyperphagia / Q000235:genetics; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010101:Oxygen Consumption / Q000187:drug effects; D010446:Peptide Fragments / Q000008:administration & dosage / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000008:administration & dosage / Q000494:pharmacology; D011333:Pro-Opiomelanocortin / Q000172:deficiency*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000521:alpha-MSH / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology
D054369:Agouti-Related Protein; D017931:DNA Primers; D054439:Ghrelin; D010446:Peptide Fragments; D010456:Peptides, Cyclic; C079282:melanotan-II; D000521:alpha-MSH; D011333:Pro-Opiomelanocortin