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In vivo evidence for inverse agonism of agouti related peptide in the central nervous system of proopiomelanocortin deficient mice

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

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 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 MTII, AgRP, and ghrelin were investigated after icv 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 wildtype mice to the anorectic effects of MTII. Hypothalamic 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. Ghrelin's action 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.

Key Words: Agouti Related Peptide (AgRP) • Proopiomelanocortin (POMC) • melanocortin receptors (MC-R) • melanotan II (MTII) • inverse agonism • food intake • indirect calorimetry

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