Objective: Energy expenditure (EE) increases in response to cold exposure, which is called cold induced thermogenesis (CIT). Brown adipose tissue (BAT) has been shown to contribute significantly to CIT in human adults. BAT activity and CIT are acutely influenced by ambient temperature. In the present study, we investigated the long-term effect of seasonal temperature variation on human CIT.Materials and Methods: We measured CIT in 56 healthy volunteers by indirect calorimetry. CIT was determined as difference between EE during warm conditions (EEwarm) and after a defined cold stimulus (EEcold). We recorded skin temperatures at eleven anatomically predefined locations, including the supraclavicular region, which is adjacent to the main human BAT depot. We analyzed the relation of EE, CIT and skin temperatures to the daily minimum, maximum and mean outdoor temperature averaged over 7 or 30 days, respectively, prior to the corresponding study visit by linear regression.Results: We observed a significant inverse correlation between outdoor temperatures and EEcold and CIT, respectively, while EEwarm was not influenced. The daily maximum temperature averaged over 7 days correlated best with EEcold (R2 = 0.123, p = 0.008) and CIT (R2 = 0.200, p = 0.0005). The mean skin temperatures before and after cold exposure were not related to outdoor temperatures. However, the difference between supraclavicular and parasternal skin temperature after cold exposure was inversely related to the average maximum temperature during the preceding 7 days (R2 = 0.07575, p = 0.0221).Conclusion: CIT is significantly related to outdoor temperatures indicating dynamic adaption of thermogenesis and BAT activity to environmental stimuli in adult humans.Clinical Trial Registration: www.ClinicalTrials.gov, Identifier NCT02682706.

Objective Human brown adipose tissue (BAT) is a thermogenic tissue activated by the sympathetic nervous system in response to cold. It contributes to energy expenditure (EE) and takes up glucose and lipids from the circulation. Studies in rodents suggest that BAT contributes to the transient rise in EE after food intake, so called diet-induced thermogenesis (DIT). We investigated the relationship between human BAT activity and DIT in response to glucose intake in 17 healthy volunteers. Methods We assessed DIT, cold induced thermogenesis (CIT) and maximum BAT activity at three separate study visits within two weeks. DIT was measured by indirect calorimetry during an oral glucose tolerance-test. CIT was assessed as the difference in EE after cold exposure of two hours duration as compared to warm conditions. Maximal activity of BAT was assessed by 18F-FDG-PET/MRI after cold exposure and concomitant pharmacological stimulation with Mirabegron. Results 17 healthy men (mean age 23.4 years, mean BMI 23.2 kg/m2) participated in the study. EE increased from 1908 (±181) kcal/24 hours to 2128 (±277) kcal/24 hours (p<0.0001, +11.5%) after mild cold exposure. An oral glucose load increased EE from 1911 (±165) kcal/24 hours to 2096 (±167) kcal/24 hours at 60 minutes (p<0.0001, +9.7%). The increase in EE in response to cold was significantly associated with BAT activity (R2=0.43, p=0.004). However, DIT was not associated with BAT activity (R2=0.015, p=0.64). Conclusion DIT after an oral glucose load was not associated with stimulated 18F-FDG uptake into BAT suggesting that DIT is independent from BAT activity in humans.

Thyroid hormone (TH) is an important regulator of mammalian metabolism and facilitates cold induced thermogenesis (CIT) in brown adipose tissue (BAT). Profound hypothyroidism or hyperthyroidism lead to alterations in BAT function and CIT. In euthyroid humans the inter-individual variation of thyroid hormones is relatively large. Therefore, we investigated whether levels of free thyroxine (T4) or free triiodothyronine (T3) are positively associated with CIT in euthyroid individuals. We performed an observational study in 79 healthy, euthyroid volunteers (mean age 25.6 years, mean BMI 23.0 kg · m-2). Resting energy expenditure (REE) was measured by indirect calorimetry during warm conditions (EEwarm) and after a mild cold stimulus of two hours (EEcold). CIT was calculated as the difference between EEcold and EEwarm. BAT activity was assessed by 18F-FDG-PET after a mild cold stimulus in a subset of 26 participants. EEcold and CIT were significantly related to levels of free T4 (R2 = 0.11, p=0.0025 and R2 = 0.13, p=0.0011, respectively) but not to free T3 and TSH. Cold induced BAT activity was also associated with levels of free T4 (R2 = 0.21, p=0.018). CIT was approximately fourfold higher in participants in the highest tertile of free T4 as compared to the lowest tertile. Additionally, free T4 was weakly, albeit significantly associated with outdoor temperature seven days prior to the respective study visit (R2 = 0.06, p=0.037). These finding suggests that variations in thyroid hormone levels within the euthyroid range are related to the capability to adapt to cool temperatures and affect energy balance.