A Role for the Endogenous Opioid β-Endorphin in Energy Homeostasis

Abstract

Proopiomelanocortin (POMC) neurons in the hypothalamus are direct targets of the adipostatic hormone leptin and contribute to energy homeostasis by integrating peripheral and central information. The melanocortin and beta-endorphin neuropeptides are processed from POMC and putatively coreleased at axon terminals. Melanocortins have been shown by a combination of pharmacological and genetic methods to have inhibitory effects on appetite and body weight. In contrast, pharmacological studies have generally indicated that opioids stimulate food intake. Here we report that male mice engineered to selectively lack beta-endorphin, but that retained normal melanocortin signaling, were hyperphagic and obese. Furthermore, beta-endorphin mutant and wild-type mice had identical orexigenic responses to exogenous opioids and identical anorectic responses to the nonselective opioid antagonist naloxone, implicating an alternative endogenous opioid tone to beta-endorphin that physiologically stimulates feeding. These genetic data indicate that beta-endorphin is required for normal regulation of feeding, but, in contrast to earlier reports suggesting opposing actions of beta-endorphin and melanocortins on appetite, our results suggest a more complementary interaction between the endogenously released POMC-derived peptides in the regulation of energy homeostasis.

Differential involvement of endogenous opioids in sucrose consumption and food reinforcement

“…However, naloxone decreased sucrose consumption after 0.5 h of access by wildtype and β-endorphin knockout mice but was completely ineffective in mice lacking enkephalin or dynorphin. We also confirmed previous findings that the β-endorphin knockout mice are obese (Appleyard, et al, 2003) but found that neither the enkephalin or dynorphin knockout mice had an obese phenotype, despite the fact that all genotypes appropriately reduced their chow intake in response to the increased caloric load provided by the sucrose solutions (Table 1). Previously, we found that Enk +/+ End −/− , Enk −/− End +/+ , and Enk −/− End −/− mice all had reduced breakpoints under a PR3, suggesting that the incentive value of food was reduced in these mice compared to wild type Enk +/+ End +/+ (Hayward, et al, 2002).…”

“…We chose to use a relatively nonspecific opioid antagonist here because the endogenous ligands are not highly specific to any one receptor. This design ensured that we would detect the activity of an opioid even if its effect on sucrose consumption was exerted through binding to multiple opioid receptors.Similar to our previous studies, we found that both male and female β-endorphin knockout mice were heavier than wild-types (Appleyard, et al, 2003). In addition, we found that subjects lacking both β-endorphin and enkephalin have the same obese phenotype as mice lacking β-endorphin alone, despite the additional loss of enkephalin.…”

Hypothalamic pro-opiomelanocortin gene delivery ameliorates obesity and glucose intolerance in aged rats

“…The prolonged anorexic response could also be attributed to potential overproduction of other peptides in addition to α-MSH, such as β-MSH and β-endorphin, both of which are normally derived from the POMC precursor. It has been suggested that these peptides also participate in the regulation of energy balance [42,43]. However, with our approach, the rAAV-mediated overexpression of Pomc in the hypothalamus did result in the transfection of neural cells outside the arcuate nucleus, most notably in the dorsomedial hypothalamic nucleus and lateral hypothalamic area.…”

The functional mu opioid receptor (OPRM1) Asn40Asp variant predicts short-term response to nicotine replacement therapy in a clinical trial

“…This result may also be explained by increased betaendorphin occupancy at the mu opioid receptor during NRT treatment among smokers with the Asp40 variant. Male knockout mice deficient in beta-endorphin exhibit hyperfagia, as well as increased body weight, 35,36 suggesting that increased central levels of beta-endorphin released by nicotine may actually suppress feeding. Other data support an association between central beta-endorphin and noveltyinduced locomotion, 37 suggesting that effects of betaendorphin on body weight may be mediated, in part, by increased physical activity.…”