Neural circuitry responsible for metabolic inhibition of adaptive thermogenesis

Project Summary The long term objective of this research is to gain an understanding of the neural
pathways and cellular mechanisms that are involved in the metabolic regulation of
energy expenditure thereby providing therapeutic targets for increasing energy
expenditure and combating obesity. The proposed research plan is a comprehensive,
logically-organized, hypothesis-driven series of studies to examine a novel mechanism
for a fundamental regulation of energy expenditure (decreased sympathetic activation of
brown adipose tissue in situations of decreased fuel availability) that may contribute to
the inability to lose body weight by caloric restriction. This model is especially relevant
since new data demonstrate brown adipose tissue in adult humans and both clinical and
non-human studies demonstrate that the functional amount of this tissue is inversely
correlated with obesity. The proposed studies will utilize functional neuroanatomical and in vivo
electrophysiological techniques to elucidate the organization and pharmacology of the
neural pathway responsible for the glucoprivation or fasting-induced decrease in
sympathetic activation of brown adipose tissue. The three specific aims will test clearly
defined hypotheses on the functional roles of specific neurochemically-defined neurons
in the ventrolateral medulla, the paraventricular nucleus of the hypothalamus, and the
raphe pallidus area in the glucoprivation-induced decrease in energy expenditure in
brown adipose tissue. Understanding the neural pathways and mechanisms that inhibit
sympathetic outflow to brown adipose tissue will provide a foundation for determining
how alterations in these pathways contribute to overweight and obesity, and will
represent an important step towards the development of therapeutic approaches to
increase energy expenditure even in the face of dietary restriction and thereby combat
obesity.