The role of brown adipose tissue on substrate metabolism and insulin sensitivity in humans

Brown adipose tissue (BAT) is a recently re-discovered tissue in humans. The role of BAT in thermogenesis and metabolic regulation has been established in rodents. However, the physiological and clinical significance of this tissue in humans has not been proven yet. The purpose of these investigations was to explore the role of BAT in whole-body energy homeostasis, glucose and lipids kinetics, insulin sensitivity, and thermoregulation in humans. To this end, we studied men with (BAT+) or without (BAT-) detectable BAT under prolonged mild cold and thermoneutral conditions using infusion of stable isotopic tracers, hyperinsulinemic-euglycemic clamps, indirect calorimetry, and positron emission tomography-computed tomography. A novel method was established to sample the supraclavicular BAT depot and white adipose tissue biopsies were collected from the subcutaneous abdominal area. During cold exposure, only BAT+ individuals demonstrated a significant increase in whole-body resting energy expenditure, free fatty acid oxidation, glucose disposal, and insulin sensitivity. BAT+ individuals also exhibited a higher increase in whole-body lipolysis during cold exposure, compared to the BAT- group, while they were protected from the cold-induced decrease in adipose tissue insulin sensitivity observed in the BAT- group. With regard to thermoregulation, BAT activity was associated with higher tolerance to cold and change in core body temperature. Functional and molecular analyses of brown and white adipose samples demonstrated the increased thermogenic capacity of BAT mitochondria and the cold-induced up-regulation of genes involved in thermogenesis and lipid metabolism in BAT. The newly established BAT biopsy technique was safe and well tolerated. These results demonstrate a physiologically significant role of BAT in whole-body energy expenditure, glucose and lipid homeostasis, insulin sensitivity, and thermoregulation in humans, and support the notion that human BAT may function as an anti-obesity and anti-diabetic tissue.