Double deletion of orexigenic neuropeptide Y and dynorphin results in paradoxical obesity in mice

Abstract

ObjectiveOrexigenic neuropeptide Y (NPY) and dynorphin (DYN) regulate energy homeostasis. Single NPY or dynorphin deletion reduces food intake or increases fat loss. Future developments of obesity therapeutics involve targeting multiple pathways. We hypothesised that NPY and dynorphin regulate energy homeostasis independently, thus double NPY and dynorphin ablation would result in greater weight and/or fat loss than the absence of NPY or dynorphin alone. Design and methodsWe generated single and double NPY and dynorphin knockout mice (NPYΔ, DYNΔ, NPYDYNΔ) and compared body weight, adiposity, feeding behaviour, glucose homeostasis and brown adipose tissue uncoupling protein-1 (UCP-1) expression to wildtype counterparts. Results Body weight and adiposity were significantly increased in NPYDYNΔ, but not in NPYΔ or DYNΔ. This was not due to increased food intake or altered UCP-1 expression, which were not significantly altered in double knockouts. NPYDYNΔ mice demonstrated increased body weight loss after a 24-h fast, with no effect on serum glucose levels after glucose injection. Conclusions Contrary to the predicted phenotype delineated from single knockouts, double NPY and dynorphin deletion resulted in heavier mice, with increased adiposity, despite no significant changes in food intake or UCP-1 activity. This indicates that combining long-term opioid antagonism with blockade of NPY-ergic systems may not produce anti-obesity effects.

Integrated circuits and molecular components for stress and feeding: implications for eating disorders

“…Additionally, the dynorphin/NPY systems have been shown to interact in modulating these behaviors. Dynorphin/NPY double knockouts have significantly greater body weight and increased adipose tissue, but no differences in food intake (Nguyen et al ). The dynorphin and kappa opioid receptor system has been identified as a major player in the stress response system, indicating that antagonism of the dynorphin system may influence both anxiety, addiction and feeding‐related behaviors.…”

Intracrine Endorphinergic Systems in Modulation of Myocardial Differentiation

“…Moreover, κ opioid receptor-null or dynorphin-null mice revealed a pronounced enhancement in overall vascular formation, associated with ectopic vascular invasion into somites at day 10.5 of embryonic development [66], indicating that dynorphin B knockout could also be used to unveil regulation of endothelial cell differentiation and pathfinding in vascular development by a κ opioid receptor system. These reports, together with other results providing wide-ranging regulation of metabolic and adaptive responses by dynorphinergic systems in dynorphin B knockout mice [67,68], suggest that given the complexity of heart development and of the associated process of cardiomyogenesis, further, more accurate studies are needed to explore the effect of dynorphin B and/or κ opioid receptor knockout on the expression of the cardiac lineage potential in targeted subset of stem cells, including CPCs. Addressing these issues may provide further insights into the potential involvement of paracrine/autocrine or intracrine patterning to explain the initial observation that high-level of endorphin gene expression could be detected in post-natal rat hearts [49,50], and that exposure to the opioid antagonist naltrexone throughout gestation was able to alter postnatal heart development [69], while dynorphin B administered to newborn rats was found to modulate heart morphogenesis [70].…”