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In Vivo Evidence for Inverse Agonism of Agouti-Related Peptide in the Central Nervous System of Proopiomelanocortin-Deficient Mice

¹ Center for the Study of Weight Regulation and Associated Disorders, Oregon Health and Science University, Portland, Oregon
² Vollum Institute, Oregon Health and Science University, Portland, Oregon
³ Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, Oregon

Address correspondence and reprint requests to Virginie Tolle, PhD, UMR549 Inserm, IFR Broca-Ste Anne, 2 ter rue d’Alesia, 75014 Paris, France. E-mail: virginie.tolle{at}broca.inserm.fr

Key Words: AgRP, Agouti-related peptide • CART, cocaine and amphetamine–related transcript • CNS, central nervous system • CRH, corticotropin-releasing hormone • DIO, diet-induced obesity • MC-R, melanocortin receptor • MC3-R, melanocortin-3 receptor • MC4-R, melanocortin-4 receptor • MSH, melanocyte-stimulating hormone • MTII, melanotan II • NPY, neuropeptide Y • PLSD, protected least squares difference • POMC, proopiomelanocortin • RER, respiratory exchange ratio

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.

RESEARCH DESIGN AND 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.

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