Christopher J. Madden - US grants

DESCRIPTION (provided by applicant): The objective of this proposal is to gain insight into the central mechanisms underlying the regulation of sympathetic control of brown adipose tissue (BAT). Sympathetic outflow to BAT plays a critical role in thermoregulation and contributes significantly to the regulation of energy expenditure. Impairments or alterations in the regulation of sympathetic output to BAT are associated with potentially life threatening pathological conditions and disease states such as hyperthermia and obesity. The specific aims of this proposal are to determine the specific central nervous system pathways involved in the regulation of sympathetic outflow to BAT during the febrile response. Inhibition of areas implicated in the regulation of sympathetic outflow to BAT will be performed during experimentally induced fever in order to assess their involvement in the febrile response. In addition, the activity of single neurons within areas found to be necessary for the febrile response will be recorded during various physiological and pharmacological manipulations in order to gain a greater understanding of the circuits involved in febrile thermogenesis. Insights gained from these experiments may eventually lead to novel approaches for treating the pathological conditions resulting from disregulation of BAT.

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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 and to determine how alterations in these mechanisms contribute to overweight and obesity and thereby increase the incidence of cardiovascular disease. This model is especially relevant since obesity is a major risk factor for cardiovascular diseases, and the functional amount of brown adipose tissue is inversely correlated with obesity. These studies utilize functional neuroanatomical and in vivo electrophysiological techniques to elucidate the organization and pharmacology of the neural pathway responsible for the glucoprivation-induced decrease in sympathetic activation of brown adipose tissue. The three specific aims will test 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. Progress thus far has indicated that neurons within the paraventricular hypothalamus provide an inhibitory input to the sympathetic pathways mediating thermogenesis 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 reverse the decrease in energy expenditure associated with dietary restriction and thereby combat obesity, thus alleviating a major risk factor for hypertension and cardiovascular disease.

Project Summary The sympathetic activation of brown adipose tissue (BAT) increases the metabolism of fatty acids within this tissue. Due to the presence of uncoupling protein-1 in the mitochondria of BAT the electrochemical gradient generated by the electron transport chain is dissipated in the absence of the production of ATP. This process which is unique to BAT (as well as inducible forms of BAT, ?beige? adipose tissue) in essence metabolizes fat to produce heat. The obvious implications of this ?fat burning? process for energy balance and body weight regulation have led to intense interest in the biological mechanisms governing this process. The activity of the sympathetic nerves innervating BAT is the principal regulator of this process. Our research has defined the fundamental neural pathways through which thermal and febrile stimuli elicit changes in the sympathetic outflow to BAT. However, relatively little is known about the neural circuits involved in the metabolic influences on BAT and how dietary components (such as the fat content of the diet) influence these regulatory circuits. In the proposed research project, we will perform an extensive series of in vivo and in vitro electrophysiological, anatomical, neuropharmacological, and Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) experiments to address specific aims that will provide new insights into the neural mechanisms responsible for the impairment of BAT activation during high fat diet (HFD) and the specific contribution of this impairment to HFD- induced weight gain. The first aim will determine the role of transient receptor potential vanilloid type 1 (TRPV1) in NTS in the impairment of BAT activation during maintenance on a high fat diet. The second aim will define the downstream projection target of the NTS that is responsible for inhibition of sympathetic output to BAT during HFD. The third aim will define the role of preprodynorphin neurons in the lateral parabrachial nucleus and kappa opioid receptor activation in the preoptic area in the impairment of BAT activation during HFD. The forth aim will define the output projection target and neurophysiological characteristics of kappa opioid receptor containing neurons of the preoptic area.