Understanding obesity by local overexpresion of neuropeptides: a viral vector based approach

Obesity is a growing problem in western society. Although in most situations energy homeostasis is regulated tightly, in modern lifestyle where plenty of food is available and there is less need to exercise, this homeostatic regulation is overruled, resulting in an increase in the prevalence of obesity. It is therefore very important to increase the knowledge of the systems involved in the regulation of energy balance. The central regulation of energy homeostasis involves a complicated neural circuitry, comprised of multiple brain areas and neuropeptides. It has become evident by pharmacological and genetic studies that the melanocortin (MC) and neuropeptide Y (NPY) systems play an important role in the regulation of energy balance. NPY and agouti (an endogenous antagonist of the MC system) are both orexigenic peptides, and chronic infusions of these neuropeptides in the brain result in obesity. Although much is known about these neuropeptidergic systems in the hypothalamus, it is not fully understood what their specific role is in the diverse hypothalamic nuclei. The aim of the studies described in this thesis was to study the contribution of the different areas in the hypothalamus on the effects of the MC and NPY system on long-term regulation of energy balance. To accomplish this, viral gene transfer was used to obtain a local, long-term overexpression of agouti or NPY in several hypothalamic areas known to be important in energy balance. Whereas an overexpression of agouti in the paraventricular nucleus (PVN) directly resulted in an increase in food intake and body weight gain, overexpression in the dorsomedial nucleus of the hypothalamus (DMH) resulted in late onset obesity, and agouti overexpression in the lateral hypothalamus (LH) only affected food intake and body weight gain when rats were given a high fat diet. NPY overexpression in the PVN also directly increased food intake and body weight gain. However, in contrast to the effects of agouti, the effects of NPY are transient, and cease when a certain body weight is reached. This indicates that NPY signaling in the PVN, and not agouti, is involved in the regulation of body weight set-point. AAV-NPY injections in the PVN also affected body temperature and activity, effects that were independent from food intake, since this was also shown in rats that were prevented to overeat. AAV-NPY injections in the LH resulted in a similar phenotype as described for the PVN, however, the effects on food intake lasted. Furthermore, the increase in food intake was due to an increase in both meal size and meal frequency, whereas NPY injections in the PVN only affected meal frequency. To summarize, although at first sight increased NPY signaling and decreased MC signaling indeed have much similarities, when carefully analyzed, the systems can be dissociated. Furthermore, the exact function of these neuropeptides depends on the hypothalamic nucleus where the peptides are expressed