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

Center for the Study of Weight Regulation and Associated Disorders, Oregon Health and Science University, Portland, Oregon, USA.
Diabetes (Impact Factor: 8.1). 02/2008; 57(1):86-94. DOI: 10.2337/db07-0733
Source: PubMed


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.
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.
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.
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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    • "NPY/AgRP neurons release three transmitters reported to stimulate feeding: AgRP, NPY, and γ-aminobutyric acid (GABA; Wu and Palmiter, 2011). AgRP was initially discovered to be a potent inhibitor of MCR function (Ollmann et al., 1997), and was subsequently characterized as an inverse agonist of MC3R and MC4R activity in vitro and in vivo (Shutter et al., 1997; Haskell-Luevano and Monck, 2001; Nijenhuis et al., 2001; Tolle and Low, 2008). However, a second in vivo experiment suggested that AgRP might function only as a competitive MCR antagonist without inverse agonist actions (Corander et al., 2011). "
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