Cold but not sympathomimetics activates human brown adipose tissue in vivo

Abstract

As potential activators of brown adipose tissue (BAT), mild cold exposure and sympathomimetic drugs have been considered as treatments for obesity and diabetes, but whether they activate the same pathways is unknown. In 10 healthy human volunteers, we found that the sympathomimetic ephedrine raised blood pressure, heart rate, and energy expenditure, and increased multiple circulating metabolites, including glucose, insulin, and thyroid hormones. Cold exposure also increased blood pressure and energy expenditure, but decreased heart rate and had little effect on metabolites. Importantly, cold increased BAT activity as measured by (18)F-fluorodeoxyglucose PET-CT in every volunteer, whereas ephedrine failed to stimulate BAT. Thus, at doses leading to broad activation of the sympathetic nervous system, ephedrine does not stimulate BAT in humans. In contrast, mild cold exposure stimulates BAT energy expenditure with fewer other systemic effects, suggesting that cold activates specific sympathetic pathways. Agents that mimic cold activation of BAT could provide a promising approach to treating obesity while minimizing systemic effects.

Fig. 1.

The effects of cold exposure and ephedrine on autonomic nervous system activity, energy expenditure, and metabolism. Healthy volunteers were treated for 1 h with cold exposure using a cooling vest or given the sympathomimetic ephedrine (1 mg/kg, i.m.) or an equal volume of saline intramuscularly. Values were measured before and after each intervention, as described in Materials and Methods. (A) SNS activation was monitored through changes in systolic BP (mmHg), diastolic BP (mmHg), and heart rate (beats per minute). (B) Metabolic rate. (C) Respiratory quotient. *P < 0.05; **P < 0.01; ***P < 0.001. Error bars are SEM.

Fig. 2.

Detection of BAT after stimulation with cold exposure, ephedrine, and saline. From a representative volunteer, brown fat FDG uptake is illustrated using coronal representations of the PET (Left), CT (Center), and combined PET–CT (Right) that includes the principal cervical, supraclavicular, and thoracic depots of BAT (green arrowheads) after stimulation with saline (Top), ephedrine 1 mg/kg (Middle), or cold exposure (Bottom), as described in Materials and Methods.

Fig. 3.

Comparison of maximal glucose uptake in brown and white adipose tissue and volume and activity of BAT after stimulation with cold exposure, ephedrine, or saline. Volunteers were exposed to cold, given ephedrine 1 mg/kg i.m., or an equal volume of saline intramuscularly, as described in Materials and Methods. Open circles are males, and filled circles are females. (A) The maximal SUV (SUVmax) of glucose in BAT and the subcutaneous white adipose tissue in the upper arm and posterior thorax. (B) Change in the volume of detectable BAT. (C) Change in detectable BAT activity.