Targeting platinum resistant disease in ovarian cancer.

Ovarian cancer is an extremely aggressive disease in which the vast majority of patients face a very poor prognosis. Although most patients initially respond to current chemotherapeutic regimens that include a combination of platinum- based therapy (cisplatin/carboplatin) and paclitaxel, the vast majority of them quickly relapse and develop increased resistance to available treatments. Thus, intrinsic and acquired chemotherapy resistance is a major obstacle in the treatment of ovarian cancer patients. Consequently, the priorities for basic and translational ovarian cancer research need to include the identification of novel therapies directed against key molecular targets and signaling pathways in platinum resistant disease. At the same time, we need to develop novel systems for drug delivery aimed at increasing the efficacy and reducing the toxicity of platinum-based treatments. Improving the current responses to platinum chemotherapy is critical not only for achieving a better outcome clinically, including a longer survival, but also for allowing patients to have a better quality of life while in treatment.

Genetic models of obesity and energy balance in the mouse.

Obesity is a health problem of epidemic proportions in the industrialized world. The cloning and characterization of the genes for the five naturally occurring monogenic obesity syndromes in the mouse have led to major breakthroughs in understanding the physiology of energy balance and the contribution of genetics to obesity in the human population. However, the regulation of energy balance is an extremely complex process, and it is quickly becoming clear that hundreds of genes are involved. In this article, we review the naturally occurring monogenic and polygenic obese mouse strains, as well as the large number of transgenic and knockout mouse models currently available for the study of obesity and energy balance.

The central melanocortin system can directly regulate serum insulin levels.

The central melanocortin system has been demonstrated to play a pivotal role in energy homeostasis. Genetic disruption of this system causes obesity in both humans and mice. Previous experiments have shown that centrally-administered melanocortin agonists inhibit food intake and stimulate oxygen consumption. Here we report that centrally-administered melanocortin agonists also inhibit basal insulin release, and alter glucose tolerance. Furthermore, increased plasma insulin levels occur in the young lean MC4-R knockout (MC4-RKO) mouse, and impaired insulin tolerance takes place before the onset of detectable hyperphagia or obesity. These data suggest that the central melanocortin system regulates not only energy intake and expenditure, but also processes related to energy partitioning, as indicated by effects on insulin release and peripheral insulin responsiveness. Previous studies emphasize the role of excess adipose mass in the development of tissue insulin resistance, leading to type II diabetes. The data presented here show that defects in the central control of glucose homeostasis may be an additional factor in some types of obesity-associated type II diabetes.

Integration of NPY, AGRP, and melanocortin signals in the hypothalamic paraventricular nucleus: evidence of a cellular basis for the adipostat.

Energy stores are held relatively constant in many mammals. The circuitry necessary for maintaining energy homeostasis should (1) sense the amount of energy stored in adipose tissue, (2) sense and integrate the multiple opposing signals regarding nutritional state, and (3) provide output regulating energy intake and expenditure to maintain energy homeostasis. We demonstrate that individual neurons within the paraventricular nucleus of the hypothalamus (PVH) are capable of detection and integration of orexigenic (neuropeptide Y [NPY]) and anorexigenic (melanocortin) signals, that NPY and melanocortins are functional antagonists of each other within the PVH in the regulation of feeding behavior, and that melanocortin administration within the PVH regulates both feeding behavior and energy expenditure. These data provide a cellular basis for the adipostat within neurons in the PVH that appear to be jointly regulated by NPY- and melanocortin-responsive neurons.

Mahogany (mg) stimulates feeding and increases basal metabolic rate independent of its suppression of agouti.

The mahogany (mg) locus originally was identified as a recessive suppressor of agouti, a locus encoding a skin peptide that modifies coat color by antagonizing the melanocyte-stimulating hormone receptor or MC1-R. Certain dominant alleles of agouti cause an obesity syndrome when ectopic expression of the peptide aberrantly antagonizes the MC4-R, a related melanocyte-stimulating hormone receptor expressed in hypothalamic circuitry and involved in the regulation of feeding behavior and metabolism. Recent work has demonstrated that mg, when homozygous, blocks not only the ability of agouti to induce a yellow coat color when expressed in the skin of the lethal yellow mouse (AY), but also the obesity resulting from ectopic expression of agouti in the brain. Detailed analysis of mg/mg AY/a animals, presented here, demonstrates that mg/mg blocks the obesity, hyperinsulinemia, and increased linear growth induced by ectopic expression of the agouti peptide. Remarkably, however, mg/mg did not reduce hyperphagia in the AY/a mouse. Furthermore, mg/mg induced hyperphagia and an increase in basal metabolic rate in the C57BL/6J mouse in the absence of AY. Consequently, although mahogany is broadly required for agouti peptide action, it also appears to be involved in the control of metabolic rate and feeding behavior independent of its suppression of agouti.