The role of NPY in the DMH in energy balance

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Neuropeptide Y (NPY) is a substance occurring naturally in the brain. The hypothalamus is one of the most important brain regions involved in the regulation of appetite. When injected directly into the hypothalamus, NPY causes dramatic hunger and obesity. NPY is found in two areas of the hypothalamus, the ARC and the DMH. ARC NPY powerfully stimulates appetite. However, the role of NPY in the DMH in the regulation of appetite is unknown. In obesity, NPY levels are decreased in the ARC but increased in the DMH. My pilot data suggests NPY in the DMH acts to reduce body weight. I will therefore determine the role of NPY in the DMH in the control of food intake and body weight. I hypothesise that NPY in the DMH is important in the regulation of appetite. I will investigate this by increasing and decreasing NPY in the DMH using gene therapy techniques. I will then study the effects of these alterations by measuring food intake, body weight and energy expenditure. These studies offer a possible exciting new insight into the control of appetite and body weight.

Technical Summary

The central dogma of hypothalamic appetite control proposes that neuropeptide Y (NPY) is exclusively an appetite stimulating factor. Intracerebroventricular (ICV) injection of NPY potently stimulates appetite. In obesity NPY is greatly reduced in the arcuate nucleus (ARC). However, in the dorsomedial hypothalamus (DMH) NPY is elevated in obesity. In a pilot study I have over expressed NPY in the DMH and observed a major chronic decrease in weight. Thus, there may be two NPY circuits with opposing effects on energy balance. I now propose to establish the role of DMH NPY in causing negative energy balance. I hypothesise that NPY in the DMH acts to reduce fat stores. I will test this hypothesis using the gene transfer vector recombinant adeno-associated virus (rAAV) to alter NPY expression in the DMH of male Wistar rats. I will initially determine the time course for changes in NPY mRNA expression within the DMH in rats fed a high fat diet. I will then use rAAV encoding NPY to over express NPY in the DMH and determine the effects on food intake, body weight and energy expenditure. Two approaches will be used to determine the physiological role of DMH NPY in the regulation of energy balance. Firstly I will use rAAV encoding antisense NPY (rAAV-NPY-AS) to prevent the rise in DMH NPY expression seen following high fat feeding. Secondly, I will use rAAV-NPY-AS to attenuate the high fat diet induced increase in DMH NPY after it has occurred. Food intake, body weight and energy expenditure will be measured. At the end of each study, body composition will be measured by both MRI and dissolution followed by chemical analysis. This work will determine the role of DMH NPY in the regulation of energy balance.

Publications

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Description Neuropeptide Y (NPY) is a substance occurring naturally in the brain. The hypothalamus is one of the most important brain regions involved in the regulation of appetite. When injected directly into the hypothalamus, NPY causes dramatically increased hunger and results in obesity and this orexigenic action of NPY has become standard dogma. However, NPY is found in two areas of the hypothalamus, the ARC and the DMN. While ARC NPY powerfully stimulates appetite, the role of NPY in the DMN in the regulation of appetite is unknown. Surprisingly, although NPY is down-regulated in the ARC in ob/ob obese mice, it is up-regulated in the DMN suggesting the role in this nucleus is opposite to that in the ARC. To test this hypothesis we used a gene therapy approach. We found that increasing expression of NPY in the DMN decreased food intake and weight gain. The same results were achieved following acute injection of NPY into the DMN; food intake was decreased rather than increased (as it is when NPY is injected into other areas). These findings may explain other studies that have inactivated the NPY gene in mice and found they become obese rather than lose weight as expected. This work has reinforced the differential role of particular neuropeptides in different circuits and thrown light on why global NPY knock-out animals and administration of systemic antagonists of NPY unexpectedly produce a variable phenotype.
First Year Of Impact 2010
Sector Pharmaceuticals and Medical Biotechnology
Impact Types Economic