Pintar, John E.

Binge eating disorder (BED) affects approximately 3% of adults in the USA and is characterized by repeated episodes of eating unusually large amounts of food in a short period of time without engaging in compensatory behaviors. Interestingly, a significant comorbidity with substance abuse exists in patients with BED. Opioid peptides are known to regulate appetitive behavior. Moreover, opioid receptor antagonists (OpRA) are used clinically in the treatment of alcohol and substance abuse. In both rats and mice, the pan OpRA LY255582 was effective in reducing BE at doses that did not affect control 24 hour intake. In rats, similar reductions in BE were observed using the mu and delta selective OpRAs LY2491481 and naltriben, respectively. The kappa selective OpRA LY2444296 was ineffective in reducing BE in rats. In order to confirm our pharmacology findings using genetic models, we evaluated BE in OpR knockout mice using a similar intermittent access paradigm. Unlike our antagonist studies, no differences in BE were observed in either the mu or delta receptor mutants compared to wildtypes. Interestingly, spontaneous free access feeding and BE were increased in the kappa receptor specific and mu‐delta‐kappa combinatorial mutants in comparison to wildtypes. Our data support that endogenous opioids modulate BE in a complex manner in rodents.

AbstractIGFs are required for normal prenatal and postnatal growth. Although actions of IGFs can be modulated by a family of IGF-binding proteins (IGFBPs) in vitro, these studies have identified a complicated pattern of stimulatory and inhibitory IGFBP effects, so that understanding relevant aspects of IGFBP action in vivo has been limited. Here we have produced a null mutation of one specific IGFBP, IGFBP-4, which is coexpressed with IGF-II early in development. Surprisingly, mutation of IGFBP-4, believed from in vitro studies to be exclusively inhibitory, leads to a prenatal growth deficit that is apparent from the time that the IGF-II growth deficit first arises, which strongly suggests that IGFBP-4 is required for optimal IGF-II-promoted growth during fetal development. Mice encoding a mutant IGFBP-4 protease (pregnancy-associated plasma protein-A), which facilitates IGF-II release from an inactive IGF-II/IGFBP-4 complex in vitro, are even smaller than IGFBP-4 mutant mice. However, the more modest IGFBP-4 growth deficit is completely restored in double IGFBP-4/pregnancy-associated plasma protein-A-deficient mice. Taken together these results indicate not only that IGFBP-4 functions as a local reservoir to optimize IGF-II actions needed for normal embryogenesis, but also establish that IGFBP-4 proteolysis is required to activate most, if not all, IGF-II mediated growth-promoting activity.