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.metabolism | thermogenesis | respiratory quotient | norepinephrine | white adipose tissue B rown adipose tissue (BAT) is a type of fat that consumes calories to generate heat. Multiple recent studies have shown that adult humans have functional BAT that can be activated in response to cold exposure in a process called nonshivering thermogenesis (1-4). In both small and large population studies (1, 2, 4, 5), there is an inverse correlation between BAT activity and obesity, suggesting that activating BAT, through pharmacological, environmental, or potentially nutritional interventions, could become a therapeutic means to treat obesity and diabetes. Indeed, human BAT energy expenditure may be a critical counterbalance to the weight gain and metabolic dysregulation caused by excess energy storage in white adipose tissue.Human BAT has a high density of both nerves and blood vessels (6), providing two general approaches to activate BAT. Based on studies in rodents, it is known that the sensation of cold by the skin and body core sends signals via peripheral neurons to the spinal cord and then up to the preoptic area of the hypothalamus for processing. From the hypothalamus, some signals go to the cerebral cortex for conscious thermal perception and localization, and others go to premotor neurons in the rostral raphe pallidus of the brainstem, projecting to neurons of the peripheral sympathetic nervous system (SNS) (reviewed in ref. 7). Ultimately, postganglionic SNS nerves release norepinephrine to activate BAT via induction of uncoupling protein-1, the tissue-specific protein that allows BAT to generate heat by uncoupling aerobic respiration from the generation of ATP.Because the endogenous pathways by cold exposure are complex and indirect, an attractive alternative for stimulation of BAT has been the use of pharmacological agents. As norepinephrine itself has too many adverse effects on the ...

Cold-induced activity of brown adipose tissue in young lean men of South-Asian and European origin

“…In our study, metabolically active BAT was found with 18 F-FDG PET-CT in 80% of all participants after 2 h of cold exposure (16-18°C), which is in line with previous publications [8]. Furthermore, the median SUV max of 18 F-FDG in BAT is similar to values reported by Cypess et al, who also investigated BAT activity in lean, healthy men [16].…”

“…our ROI). Cypess et al used the same threshold [16]. However, Vosselman et al used a threshold of 1.5 g/ml [17] and van Marken Lichtenbelt et al reported that they used a 'set threshold' [8], whereas Carey et al and Ouellet et al considered an SUV >1.0 g/ml as BAT [18,19].…”

Pioglitazone reduces cold-induced brown fat glucose uptake despite induction of browning in cultured human adipocytes: a randomised, controlled trial in humans

“…Because glucose is not the primary substrate, BAT activity based on [ 18 F]FDG uptake may underestimate and potentially miss components of BAT energy metabolism under certain physiological conditions. While [ 18 F]FDG-PET-based assessments of human BAT activity in response to acute [20,21,38,42] and chronic [2,4] cold exposure have reflected the expected outcomes based on rodent experiments, this study indicates that there are species differences for other adaptive stimuli. Although we have shown that pioglitazone reduced coldstimulated BAT glucose uptake, we cannot definitively claim that fat oxidative capacity also decreased.…”

“…This study consisted of two parts: (1) a human primary cell culture study to determine whether pioglitazone could induce adipogenesis and browning of primary adipocytes derived from subacromioclavicular adipose biopsies and (2) upon determination that pioglitazone induced browning in vitro, a clinical trial to examine whether prolonged (4 weeks) treatment of humans with pioglitazone would increase coldstimulated BAT activity, assessed by glucose uptake using [ 18 [20,21] and would therefore be expected to contain a mixture of adipocyte and pre-adipocyte subtypes, including brown/beige adipocytes, and is directly relevant to informing our subsequent clinical trial in which upper thoracic and cervical adipose tissue is the primary region of interest.…”

Ephedrine activates brown adipose tissue in lean but not obese humans

“…In humans it is currently not known whether a pharmacological agent can activate BAT, as previous studies have used inconclusive experimental techniques [9,20,21] or observed no effect of drugs on BAT activity [22,23]. Since BAT activation is mediated by sympathetic efferents predominantly via β-adrenergic receptors in BAT [1], sympathomimetic drugs represent a relevant drug class for investigation.…”