The hypothalamic melanocortin system is unique among neuropeptide systems controlling energy homeostasis, in that both anorexigenic proopiomelanocortin ( @entity11982 )-derived and orexigenic @entity29930 ( @entity29930 )-derived ligands act at the same receptors, namely melanocortin 3 and 4 receptors (MC3/4R). @entity29930 clearly acts as a competitive antagonist at @entity39116 and @entity26472 but may also have an inverse agonist action at these receptors. The physiological relevance of this remains uncertain. We generated a @entity19 lacking both @entity11982 and @entity29930 [double knockout (DKO) @entity19 ]. Phenotyping was performed in the absence and presence of glucocorticoids, and the response to central peptide administration was studied. The phenotype of DKO @entity19 is indistinguishable from that of @entity19 lacking @entity11982 alone, with both exhibiting highly similar degrees of @entity7298 and @entity101 , fat, and lean mass compared with wild-type controls. After a 24-h fast, there was no difference in the refeeding response between @entity11982 (-/-) and DKO @entity19 . Similarly, @entity2819 supplementation caused an equivalent increase in food intake and body weight in both genotypes. Although the central administration of [ @entity41039   , @entity24561   ]-a-MSH to DKO @entity19 caused a @entity393 and an increase in brown adipose tissue @entity4305 expression, both of which could be antagonized with the coadministration of @entity29930 , there was no effect of @entity29930 alone. These data suggest @entity29930 acts predominantly as a melanocortin antagonist. If @entity29930 has significant melanocortin-independent actions, these are of insufficient magnitude in vivo to impact any of the detailed phenotypes we have measured under a wide variety of conditions.

Loss of agouti-related peptide does not significantly impact the phenotype of @entity19 XXXX deficiency.

@entity101 :: ('MESH:D006973', 'Disease') :: ['increased body length'] @entity11982 :: ('18976(Tax:10090)', 'Gene') :: ['POMC', 'Pomc'] @entity24561 :: ('CHEBI:32500', 'Chemical') :: ['d-Phe'] @entity19 :: ('10090', 'Species') :: ['mice', 'mouse'] @entity29930 :: ('11604(Tax:10090)', 'Gene') :: ['AgRP', 'Agouti related-peptide'] @entity26472 :: ('17202(Tax:10090)', 'Gene') :: ['MC4R'] @entity7298 :: ('MESH:D006963', 'Disease') :: ['hyperphagia'] @entity41039 :: ('CHEBI:36405', 'Chemical') :: ['Nle'] @entity2819 :: ('MESH:D003345', 'Chemical') :: ['corticosterone'] @entity4305 :: ('22227(Tax:10090)', 'Gene') :: ['Ucp1'] @entity393 :: ('MESH:D034381', 'Disease') :: ['decrease in food intake'] @entity39116 :: ('17201(Tax:10090)', 'Gene') :: ['MC3R']
@entity11982 :: (18976(Tax:10090),Gene) :: ['POMC']
