Correspondence matthias.betz@usb.ch (M.J.B.), irene.burger@usz.ch (I.A.B.), christian-wolfrum@ethz.ch (C.W.) In Brief Through genetic and pharmacological in vivo and in vitro approaches, Balaz et al. show that the mevalonate pathway is important for adipocyte browning. The importance of this pathway is supported by a retrospective clinical study and a small volunteer trial with fluvastatin. The authors identify geranylgeranyl pyrophosphate as the key mevalonate intermediate driving adipocyte browning. SUMMARYRecent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modu-lating brown adipocyte functionality and systemic metabolism.

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Background: Hypothyroidism is a frequent endocrine disorder with common symptoms of increased cold sensitivity and unintended weight gain, indicating changes in energy expenditure (EE) and response to cold exposure. Thyroid hormones (TH) play an important role for proper function of brown adipose tissue (BAT) and cold-induced thermogenesis (CIT) in rodents, but the role of hypothyroidism on CIT in humans is uncertain. Methods: This was a prospective observational study. Forty-two patients presenting with subclinical or overt hypothyroidism in whom TH replacement was planned were recruited. Thirty-three patients completed the study. Thermogenesis was measured by indirect calorimetry during warm conditions and after a mild cold stimulus of 90 minutes, both during the hypothyroid state and after at least three months of sufficient TH replacement. CIT was determined as the difference between EE during mildly cold and warm conditions. The primary endpoint was the change of CIT between the hypothyroid and euthyroid state. Results: EE during warm conditions increased from a median of 1330 (interquartile range [IQR] 1251–1433) kcal/24 hours in the hypothyroid state to a median of 1442 (IQR 1294–1579) kcal/24 hours in the euthyroid state (+8.5%; p = 0.0002). EE during mild cold exposure increased from 1399 (IQR 1346–1571) kcal/24 hours to 1610 (IQR 1455–1674) kcal/24 hours (+15%; p < 0.0001). The median CIT was 55 (IQR 1–128) kcal/24 hours at the baseline visit, after restoration of euthyroidism CIT increased by 102% to a median of 111 (IQR 15.5–200) kcal/24 hours ( p = 0.011). Serum levels of free thyroxine at the respective visit and mean outdoor temperature during the preceeding 30 days were significantly associated with CIT ( p = 0.021 and p = 0.001, respectively). Conclusion: Restoring euthyroidism significantly increases CIT in hypothyroid humans.

Background Brown adipose tissue (BAT) has been proposed as a target to treat obesity and metabolic disease. Currently, 18F‐Fluordeoxyglucose positron emission tomography (FDG‐PET) is the standard for BAT‐imaging. MRI might be a promising alternative, as it is not associated with ionizing radiation, offers a high resolution, and allows to discriminate different types of soft tissue. Purpose We sought to evaluate whether supraclavicular BAT (scBAT) volume, fat‐fraction (FF), and relaxation rate (R2*) determined by MRI can predict its metabolic activity, which was assessed by measurement of cold‐induced thermogenesis (CIT). Study Type Prospective cohort study. Subjects Twenty healthy volunteers (9 female, 11 male), aged 18–47 years, with a body mass index (BMI) of 18–30 kg/m2. Field Strength/Sequence Multiecho gradient MRI for water–fat separation was used on a 3T device to measure the FF and T2* of BAT. Assessment Prior to imaging, CIT was determined by measuring the difference in energy expenditure (EE) during warm conditions and after cold exposure. Volume, FF, and R2* of scBAT was assessed and compared with CIT. In 11 participants, two MRI sessions with and without cold exposure were performed and the dynamic changes in FF and R2* assessed. Statistical Tests Linear regression was used to evaluate the relation of MRI measurements and CIT. P‐values below 0.05 were considered significant; data are given as mean ± SD. Results R2* correlated positively with CIT (r = 0.64, R2 = 0.41 P = 0.0041). Volume and FF did not correlate significantly with CIT. After mild cold exposure EE increased significantly (P = 0.0002), with a mean CIT of 147 kcal/day. The mean volume of scBAT was 72.4 ± 38.4 ml, mean FF was 74.3 ± 5.8%, and the mean R2* (1/T2*) was 33.5 ± 12.7 s‐1. Data Conclusion R2* of human scBAT can be used to estimate CIT. FF of scBAT was not associated with CIT. Level of Evidence: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;50:1160–1168.