Brown fat does not cause cachexia in cancer patients: A large retrospective longitudinal FDG-PET/CT cohort study.

BACKGROUND: Brown adipose tissue (BAT) is a specialized form of adipose tissue, able to increase energy expenditure by heat generation in response to various stimuli. Recently, its pathological activation has been implicated in the pathogenesis of cancer cachexia. To establish a causal relationship, we retrospectively investigated the longitudinal changes in BAT and cancer in a large FDG-PET/CT cohort. METHODS: We retrospectively analyzed 13 461 FDG-PET/CT examinations of n = 8 409 patients at our institution from the winter months of 2007-2015. We graded the activation strength of BAT based on the anatomical location of the most caudally activated BAT depot into three tiers, and the stage of the cancer into five general grades. We validated the cancer grading by an interreader analysis and correlation with histopathological stage. Ambient temperature data (seven-day average before the examination) was obtained from a meteorological station close to the hospital. Changes of BAT, cancer, body mass index (BMI) and temperature between the different examinations were examined with Spearman's test and a mixed linear model for correlation, and with a causal inference algorithm for causality. RESULTS: We found n = 283 patients with at least two examinations and active BAT in at least one of them. There was no significant interaction between the changes in BAT activation, cancer burden or BMI. Temperature changes exhibited a strong negative correlation with BAT activity (ϱ = -0.57, p<0.00001). These results were confirmed with the mixed linear model. Causal inference revealed a link of Temperature ➜ BAT in all subjects and also of BMI ➜ BAT in subjects who had lost weight and increased cancer burden, but no role of cancer and no causal links of BAT ➜ BMI. CONCLUSIONS: Our data did not confirm the hypothesis that BAT plays a major role in cancer-mediated weight loss. Temperature changes are the main driver of incidental BAT activity on FDG-PET scans.

Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation.

Recent 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 modulating brown adipocyte functionality and systemic metabolism.

Author Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

In the version of this article originally published, the months on the axis labeled projected month of conception in Fig. 1a were out of order. April and March should have been the first and last months listed, respectively. The error has been corrected in the print, PDF and HTML versions of this article.

Publisher Correction: Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

In the version of this article originally published, the bars in the mean temperature graph in Fig. 1a were incorrectly aligned. The left-most bar should have been aligned with the Apr label on the projected month of conception axis. The error has been corrected in the print, PDF and HTML versions of this article.

Cold-induced epigenetic programming of the sperm enhances brown adipose tissue activity in the offspring.

Recent research has focused on environmental effects that control tissue functionality and systemic metabolism. However, whether such stimuli affect human thermogenesis and body mass index (BMI) has not been explored. Here we show retrospectively that the presence of brown adipose tissue (BAT) and the season of conception are linked to BMI in humans. In mice, we demonstrate that cold exposure (CE) of males, but not females, before mating results in improved systemic metabolism and protection from diet-induced obesity of the male offspring. Integrated analyses of the DNA methylome and RNA sequencing of the sperm from male mice revealed several clusters of co-regulated differentially methylated regions (DMRs) and differentially expressed genes (DEGs), suggesting that the improved metabolic health of the offspring was due to enhanced BAT formation and increased neurogenesis. The conclusions are supported by cell-autonomous studies in the offspring that demonstrate an enhanced capacity to form mature active brown adipocytes, improved neuronal density and more norepinephrine release in BAT in response to cold stimulation. Taken together, our results indicate that in humans and in mice, seasonal or experimental CE induces an epigenetic programming of the sperm such that the offspring harbor hyperactive BAT and an improved adaptation to overnutrition and hypothermia.

Ultra-low-dose coronary artery calcium scoring using novel scoring thresholds for low tube voltage protocols-a pilot study.

Aims: To determine if tube-adapted thresholds for coronary artery calcium (CAC) scoring by computed tomography at 80 kilovolt-peak (kVp) tube voltage and 70-kVp yield comparable results to the standard 120-kVp protocol. Methods and results: We prospectively included 103 patients who underwent standard scanning with 120-kVp tube voltage and additional scans with 80 kVp and 70 kVp. Mean body mass index (BMI) was 27.9 ± 5.1 kg/m2. For the lowered tube voltages, we applied novel kVp-adapted thresholds for calculation of CAC scores and compared them with standard 120-kVp scans using intraclass correlation and Bland-Altman (BA) analysis. Furthermore, risk-class (CAC score 0/1-10/11-100/101-400/>400) changes were assessed. Median CAC score from 120-kVp scans was 212 (interquartile range 25-901). Thirteen (12.6%) patients had zero CAC. Using the novel kVp-adapted thresholds, CAC scores derived from 80-kVp scans showed excellent correlation (r = 0.994, P < 0.001) with standard 120-kVp scans with BA limits of agreement of -235 (-39.5%) to 172 (28.9%). Similarly, for 70-kVp scans, correlation was excellent (r = 0.972, P < 0.001) but with broader limits of agreement of -476 (-85.0%) to 270 (48.2%). Only 2 (2.8%) reclassifications were observed for the 80-kVp scans in patients with a BMI <30 kg/m2 (n = 71), and 2 (6.1%) for the 70-kVp scans in patients with a BMI <25 kg/m2 (n = 33). Mean effective radiation dose was 0.60 ± 0.07 millisieverts (mSv), 0.19 ± 0.02 mSv, and 0.12 ± 0.01 mSv for the 120-kVp, 80-kVp, and 70-kVp scans, respectively. Conclusion: The present study suggests that CAC scoring with reduced peak tube voltage is accurate if kVp-adapted thresholds for calculation of CAC scores are applied while offering a substantial further radiation dose reduction.

Ovarian Hyperstimulation and Oocyte Harvesting Prior to Systemic Chemotherapy-A Possible Pitfall in 18F-FDG PET/CT Staging of Oncologic Patients.

A 33-year-old woman with Hodgkin disease Ann Arbor stage IIA underwent baseline F-FDG PET/CT scanning. The scan showed gross multicystic enlargement of both ovaries and a nodule at the edge of the right ovary with intense FDG uptake (SUVmax = 14.8). Differential diagnosis would include ovarian lymphoma manifestation, endometrioma, and ovarian or pelvic neoplasia. However, chart analysis revealed previous superstimulation with gonadotropins and gonadotropin release hormone antagonist, and transvaginal oocyte retrieval the day before FDG PET/CT. This led to the diagnosis of ovarian hyperstimulation syndrome, with the FDG-avid focus representing a hemorrhagic follicle after transvaginal oocyte retrieval procedure.

Ipilimumab-Induced Adrenalitis: A Possible Pitfall in 18F-FDG-PET/CT.

Ipilimumab is a monoclonal antibody against the inhibitory CTLA-4 receptor expressed on T cells. It provokes an upregulation of the immune system. This substance was approved by the US Food and Drug Administration in 2011 and is since increasingly used as a targeted therapeutic approach for metastasized melanoma. Ipilimumab is known to cause neuroendocrine disorders, such as hypophysitis and adrenal insufficiency. Our case of a 79-year-old patient represents an important imaging pitfall. Imaging findings of newly symmetrically and smoothly enlarged, hypermetabolic adrenal glands in the setting of previous ipilimumab therapy represent drug-induced adrenalitis and not metastatic disease.