As obesity is becoming a major health concern worldwide, the search for therapies targeted towards decreasing overweight attracts unprecedented interest. Treatments for obesity involve decreasing energy uptake and/or increasing energy expenditure. When activated by cold and sympathetic nervous system stimulation, brown adipose tissue (BAT) increases energy expenditure by using fatty acids and glucose to produce heat. The thermogenic ability of BAT has been reported for decades in rodents. Until recently, it was assumed that functional BAT existed only in human infants and disappeared thereafter. As BAT has recently been found in adult humans, interest in increasing the amount and activity of BAT has grown, as a possible approach to increase energy expenditure and decrease obesity. There are however difficulties associated with studying BAT in vivo. 18F-fluorodeoxyglucose positron emission tomography coupled with CT scan (18F-FDG PET-CT) is currently the only technology available to detect human BAT in vivo, but these machines are rare, the experiments expensive, and because of radiation exposure it is not possible to do repeated studies in an individual under various conditions. The present proposal is based on the fact that activation of BAT is accompanied by an increase in BAT blood flow. This increase in blood flow is thought to deliver additional substrates and oxygen to the BAT and is necessary for BAT-induced thermogenesis. Contrast-enhanced ultrasound involves the intravenous infusion of echogenic microbubbles during the ultrasound procedure, allowing the estimation of tissue blood flow. We propose to use contrast-enhanced ultrasound (CEU) to detect and monitor functional BAT in mice and humans. In preliminary data, we report that CEU detects blood flow in mice and human BAT, before and after BAT stimulation. We propose to 1.characterize BAT perfusion in mice. 2. Validate CEU in the detection of BAT in humans. In mice, after validation of CEU-estimated BAT blood flow and volume, the effect of aging or obesity on BAT perfusion, volume and thermogenesis will be investigated. In humans, the relationship between CEU-derived BAT blood flow and the metabolic activity of BAT will be characterized. For this purpose, 20 human volunteers will undergo CEU before and after cold exposure and 18F-FDG PET-CT after cold exposure. The CEU-estimated blood flow in BAT (and white adipose tissue) will be compared to the metabolic activity detected by PET. The CEU-calculated supraclavicular BAT volume will be compared to that calculated by PET. Contrast-enhanced ultrasound is noninvasive, easily available, and affordable. If the proposal is successful, CEU may be a non irradiating, widely available technique to detect BAT and monitor potential therapies that increase functional BAT.

Public Health Relevance

As obesity is reaching worldwide proportion, researchers have become interested in activating brown adipose tissue, a fat tissue that consumes fat and sugar to produce heat and may help weight loss. The only method to detect brown adipose tissue in humans, PET scan, uses radioactivity and is sparsely available and expensive. We propose to develop a noninvasive, easily available, scalable and affordable method to detect and monitor brown adipose tissue based on ultrasound.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZDK1-GRB-7 (M1))
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Haft, Carol R
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Massachusetts General Hospital
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