Discussion
shivering, rheumatoid arthritisPrednisone
Based on preclinical studies using Two trials in human subjects, which coincided with our study, investigated the effect of oral GCs on BAT activity in humans. The acute treatment over 24 h with a total dose of 30 mg prednisone led to higher cold-induced thermogenesis (CIT) and BAT activity as compared to placebo in a small cohort of six healthy men.In our current placebo controlled, randomised, cross-over trial we used a high daily dose of prednisone equivalent to ten times the physiologic production rate of cortisol per day. This treatment over the course of one week did not change the activity of human BAT. Several differences in experimental and cooling protocols between the three trials may explain the respective results.The amount of prednisone used in our trial was almost three-fold higher than in the Australian study, which clearly impacts its metabolic effects.The normal room temperature in most animal facilities is around 21 °C and thus well below the thermoneutral zone of mice. Humans on the other hand live at thermoneutral temperatures most of the time. In a recent study, corticosterone reduced UCP1 protein levels in mice kept at 30 °C but not in those kept at 21 °C,Currently, most clinical trials use In addition to these physiological data, we analysed the molecular changes elicited by prednisone in scBAT with RNA sequencing. In line with the metabolic measurements, we did not observe statistically significant changes in BAT specific markers or the amount of brown adipocytes as determined by BATLAS score.Data from experiments in mice indicate that continuous corticosterone exposure reduces BAT activity whereas an administration following the normal circadian rhythm does not alter CIT.To support our findings from acute GC exposure of healthy volunteers we analysed two additional patient cohorts. We assessed BAT activity in patients who had been treated for at least three months with GCs and were then weaned from treatment. In this small cohort, BAT activity and CIT were not different during GC treatment as compared to the control period. BAT activity was generally lower than in healthy volunteers. Moreover, we analysed retroperitoneal adipose tissue samples from patients undergoing adrenal surgery. Patients suffering from endogenous GC excess did not exhibit different amounts of retroperitoneal BAT as compared to patients with other benign adrenal masses. These findings are in line with two prospective studies which investigated the metabolic effects of glucocorticoid treatment in patients suffering from rheumatoid arthritisPrednisone treatment increased the REE which has been described previously.We cannot exclude low grade shivering during the cooling as we did not use electromyography but observed and asked participants for signs and symptoms of cold-induced shivering. While EMG measurements can identify shivering earlier than visual assessment or measurement of EE, a direct comparison of these methods with EMG performed well to reliably detect shiveringOur study is limited by the fact that we only recruited male participants and we can therefore not draw any conclusions on the effect of GCs on BAT in women. The sample size was reasonable for a study investigating basic metabolic physiology but is of course much smaller than in an epidemiologic cohort study. Given the design of the trial, we can only speculate on the reasons behind the increase in REE and central skin temperature. Glucocorticoids increase simultaneously both lipolysis and triglyceride synthesis in white adipocytes.Our trial has several strengths: Our cohort size was larger than that of previous studies and guided by sample size calculations. This gives the study sufficient power to detect clinically relevant changes in BAT activity. As we expected a reduction in BAT activity, we pre-screened participants for substantial levels of CIT, thereby ensuring at least moderate cold-induced BAT activity was present. In addition, we avoided the warm summer months to reduce confounding effects. In line with previous studies, we analysed FDG uptake into BAT. This parameter has recently been challenged as a surrogate marker of BAT activity as it may be altered despite normal BAT function.In conclusion, short-term treatment with prednisone increased EE in healthy men possibly by altering SKM calcium cycling. Cold-induced BAT activity was not affected by GC treatment which indicates that the unfavourable metabolic effects of GCs are independent from thermogenic adipocytes. Future work should investigate how GCs increase resting EE.