Obesity is a major health problem in the United States affecting a large portion of the population. It can lead to serious diseases such as heart failure, stroke and diabetes. A more detailed understanding of the homeostatic regulation of weight is required to find the best method of both preventing and treating this serious disease. POMC neurons in the hypothalamus have been demonstrated to play a critical role m weight homeostasis. Melanocortins inhibit feeding and are essential for appropriate weight homeostasis as mice deficient in melanocortin signaling are obese. The effects of beta-endorphin on weight homeostasis are less clear. Surprisingly, our preliminary results indicate that mice lacking beta-endorphin are also obese. The first goal of this grant is to establish the mechanism of the obesity in beta-endorphin deficient mice and to determine whether this obesity is additive with MC4 receptor deficient mice. NPY modulates the release of alpha-MSH and beta-endorphin from these neurons, and opioid antagonists have been shown to block NPY stimulated food intake. We therefore plan to test the hypothesis that beta-endorphin is required for the action of NPY and predict that mice lacking beta-endorphin will be deficient in NPY- stimulated feeding. The ventrobasal hypothalamus has an inhibitory tone on weight homeostasis and high levels of expression of leptin receptors. Both POMC and NPY neurons have cell bodies in this region and express leptin receptors. In addition to the melanocortins, POMC neurons also express CART, a transmitter shown to potently inhibit feeding and predicted to play an important role in weight homeostasis, as well as potentially unidentified transmitters. We hypothesize that other transmitters in the POMC neurons, aside from the melanocortins, are important for weight homeostasis and leptin action. To test this, we propose to remove all signaling through these POMC neurons by specifically ablating the POMC neurons in adult mice. Weight homeostasis and leptin function in these mice will then be compared to mice deficient solely in POMC signaling.
| Low, Malcolm J; Hayward, Michael D; Appleyard, Suzanne M et al. (2003) State-dependent modulation of feeding behavior by proopiomelanocortin-derived beta-endorphin. Ann N Y Acad Sci 994:192-201 |
| Appleyard, Suzanne M; Hayward, Michael; Young, Juan I et al. (2003) A role for the endogenous opioid beta-endorphin in energy homeostasis. Endocrinology 144:1753-60 |
