Eva Szentirmai - US grants

DESCRIPTION (provided by applicant): The interactions between sleep and metabolism have been described in health and disease; however, the mechanisms and tissues mediating this interplay remain unclear. Brown adipose tissue (BAT) plays a critical role in maintaining metabolic homeostasis by regulating energy expenditure, glucose disposal and heat production. Brown fat has become the focus of intensive research after the detection of functional BAT in human adults five years ago; this recent advance makes the proposed research particularly timely. BAT activation is associated with the suppression of body weight and with a healthy metabolic phenotype. Loss of BAT function is linked to multiple metabolic disorders, such as obesity and type 2 diabetes. The long-term goal is to identify the mechanisms that underlie the reciprocal relationship between sleep and sleep loss on the one side, and metabolism and metabolic disorders on the other. The goal of this proposal is to investigate a novel peripheral mechanism of sleep signaling in which the metabolic activity of BAT plays a central role. The central hypothesis is that sleep loss increases sympathetic outflow to BAT and stimulates the alternative activation of resident macrophages in BAT leading to increased BAT thermogenesis. BAT heat production, in turn, facilitates recovery sleep after sleep loss via the activation of the nucleus tractus solitarius (NTS). The central hypothesis is based on preliminary studies demonstrating that sleep loss activates BAT thermogenesis which is critical for the subsequent recovery sleep. Three specific aims will test the central hypothesis. Specific Aim 1 will identify the mechanisms of sleep loss-induced BAT activation. We will determine the role of sympathetic efferents and alternatively activated (M2) macrophages. Specific Aim 2 will determine the contribution of BAT sympathetic nerves and M2 macrophages to sleep and metabolic responses to sleep loss. Specific Aim 3 will determine the role of NTS in the somnogenic signaling from BAT. The approach is innovative because it focuses on a novel mechanism through which sleep and the metabolic activity of a peripheral organ are reciprocally connected. Sleep loss is associated with increased risk of obesity, diabetes, cardiovascular diseases, cancer, as well as increased all-cause mortality. It impairs cognitive and behavioral performance posing a significant burden to society in terms of property damage, lost productivity, personal injury, and death. The proposed research is significant, because understanding the physiological mechanisms that underlie recovery from sleep loss will lead to new treatment strategies to prevent negative health outcomes associated with poor sleep.

PROJECT SUMMARY Signals from peripheral tissues play an important role in aligning sleep-wake activity with the metabolic, nutri- tional and immune status of the organism. The intestinal microbiota is an essential source of such signals through the production of bacterial metabolites, e.g., short-chain fatty acids (SCFAs), and the release of bacterial cell wall components, lipopolysaccharide (LPS) and peptidoglycans. The long-term objective is to identify mechanisms of microbiota-brain communications and its relevance to sleep regulation. The objective of the present proposal is to investigate the newly discovered sleep-promoting viscerosensory mechanism in the hepatoportal region. Activation of hepatoportal sensors by SCFAs and bacterial cell wall products is a potent sleep-promoting signal. The central hypothesis is that bacterial products, such as LPS that translocate from the intestinal lumen to the liver via the portal vein, activate hepatic macrophages. Macrophages, in turn, secrete prostaglandins locally, which activate the sensory neurons of the hepatic vagus. Vagus carries somnogenic signal to the nucleus tractus solitarius, a component of brain stem sleep circuits. In three specific aims, we will 1) determine the role of hepatic macrophages in LPS-induced sleep in macrophage-depleted rats, 2) determine the contribution of hepatic prostaglandin E2 in sleep signaling 3) determine the contribution of hepatic vagal afferents in hepatoportal sleep induction. The concept of microbiota-gut-brain axis is viewed as a major paradigm shift in neuroscience. Changes in the composition of microbiota as well as increased translocation of microbial products to the systemic circulation are related to pathological conditions, including disorders of the central nervous system. Identifying the role of bacterial products in sleep regulation is important because the gut flora is susceptible to changes in diet, environment, food additives and antibiotic treatment, which could lead to altered sleep, but it can also provide an easily accessible target for translational research to improve sleep.