Terence Jones

Identification of Brown Adipose Tissue Using MR Imaging in a Human Adult With Histological and Immunohistochemical Confirmation

OBJECTIVE Manipulation of human brown adipose tissue (BAT) represents a novel therapeutic option for diabesity. The aim of our study was to develop and test a novel magnetic resonance (MR) imaging-based method to identify human BAT, delineate it from white adipose tissue, and validate it through immunohistochemistry. DESIGN A 25-year old Caucasian female with hyperparathyroidism-jaw tumor syndrome underwent parathyroidectomy. An (18)fluoro-2-deoxyglucose positron emission tomography (PET)-computed tomography (CT) scan performed after surgery ruled out malignancy but showed avid uptake within the mediastinum, neck, supraclavicular fossae, and axillae, consistent with BAT. Immunohistochemical staining using uncoupling protein-1 antibody was performed on one fat sample obtained from the suprasternal area during parathyroidectomy. Subsequently, serial MR scans were performed. Retrospectively, regions of interest (ROIs) were identified on MR corresponding to areas of high uptake on PET-CT. Prospectively, ROIs were identified on MR based on signal intensity and appearance and compared with PET-CT. RESULTS Of 111 retrospectively identified ROIs from PET-CT, 93 (83.8%) showed corresponding low MR signal: 25 of 25 mediastinum (100%), 29 of 31 neck (93.5%), 31 of 41 supraclavicular (75.6%), and 8 of 14 axillae (57%). Prospectively, 47 of 54 ROIs identified on MR (87%) showed a corresponding increased uptake on PET-CT. Serendipitously, the sample obtained at surgery corresponded with high uptake and low signal on subsequent PET and MR, respectively, and immunohistochemistry confirmed BAT. CONCLUSION We provide the first report for the reliable use of MR to identify BAT in a living human adult, with histological/immunohistochemical confirmation. Our data demonstrate proof of concept to support the development of MR as a safe, reproducible imaging modality for human BAT.

Brown fat depots in adult humans remain static in their locations on PET/CT despite changes in seasonality

Active brown adipose tissue (BAT) in humans has been demonstrated through use of positron emission tomography with 2‐deoxy‐2‐(fluorine‐18) fluoro‐D‐glucose integrated with computed tomography (18F‐FDG PET/CT) scans. The aim of our study was to determine whether active human BAT depots shown on 18F‐FDG PET/CT scans remain static in their location over time. This was a retrospective study. Adult human subjects (n = 15) who had had 18F‐FDG PET/CT imaging (n = 38 scans in total) for clinical reasons were included on the basis of 18F‐FDG uptake patterns consistent with BAT activity. For each subject, 18F‐FDG BAT uptake pattern on serial 18F‐FDG PET/CT images was compared to an index 18F‐FDG PET/CT image with the largest demonstrable BAT volume. Object‐based colocalization was expressed as Manders correlation coefficient (where 1 = 100% overlap, 0 = no overlap). Distribution of 18F‐FDG BAT activity over time and across multiple 18F‐FDG BAT scans was equivalent in 60% (n = 9) of the subjects. The degree of consistency in the pattern of 18F‐FDG BAT uptake in each subject over time was greater than expected by chance in 87% (n = 13) of the subjects (pair‐wise agreement 75–100%, Fleiss’ κ 0.4–1). The degree of BAT colocalization on serial scans was greater than that expected by chance in 93% (n = 14) of the subjects (mean Manders coefficient 0.81 ± 0.21 [95% CI]). To our knowledge, our study provides the most conclusive evidence to date to support the notion that active BAT depots in humans (volumes and activities of which were measured through use of 18F‐FDG PET/CT scans) remain static in location over sustained periods.

Identification of an optimal threshold for detecting human brown adipose tissue using receiver operating characteristic analysis of IDEAL MRI fat fraction maps

PURPOSE Lower fat fraction (FF) in brown adipose tissue (BAT) than white adipose tissue (WAT) has been exploited using Dixon-based Magnetic Resonance Imaging (MRI) to differentiate these tissues in rodents, human infants and adults. We aimed to determine whether an optimal FF threshold could be determined to differentiate between BAT and WAT in adult humans in vivo. METHODS Sixteen volunteers were recruited (9 females, 7 males; 44.2 ± 19.2 years) based on BAT uptake on 18F-FDG PET/CT. Axial 3-echo TSE IDEAL sequences were acquired (TR(ms)/TE(ms)/matrix/NEX/FoV(cm) = 440/10.7-11.1/512 × 512/3/30-40), of the neck/upper thorax on a 3T HDxt MRI scanner (GE Medical Systems, Milwaukee, USA), and FF maps generated from the resulting water- and fat-only images. BAT depots were delineated on PET/CT based on standardized uptake values (SUV) >2.5 g/ml, and transposed onto FF maps. WAT depots were defined manually within subcutaneous fat. Receiver operating characteristic (ROC) analyses were performed, and optimal thresholds for differentiating BAT and WAT determined for each subject using Youdens J statistic. RESULTS There was large variation in optimal FF thresholds to differentiate BAT and WAT between subjects (0.68-0.85), with great variation in sensitivity (0.26-0.84) and specificity (0.62-0.99). FF was excellent or good at separating BAT and WAT in four cases (area under the curve [AUC] 0.84-0.92), but poor in 10 (AUC 0.25-0.68). CONCLUSION Although this technique was effective at differentiating BAT and WAT in some cases, no universal cut-off could be identified to reliably differentiate BAT and WAT in vivo in adult humans on the basis of FF.

Effects of visfatin on brown adipose tissue energy regulation using T37i cells

&NA; The role of brown adipose tissue (BAT) in pathological states of energy homeostasis and impaired adipocyte function, such as obesity has been a major area of research interest in recent years. Herein, we sought to determine the direct effects of adipokines, visfatin and leptin on BAT thermogenesis. The effects of mouse recombinant visfatin, nicotinamide mononucleotide (NMN) and leptin with or without FK866 were studied on differentiated T37i cells. Treated cells were analyzed for key genes and proteins regulating BAT [UCP‐1, PRD1‐BF1‐RIZ1 homologous domain‐containing 16 (PRDM‐16), PPARgamma‐coactivator‐1alpha (PGC‐1&agr;) and receptor‐interacting protein 140 (RIP‐140)] using quantitative PCR and western blot analysis. Data is presented as mean P‐values. Both visfatin and leptin had significant concentration dependent effects on thermogenesis in brown pre‐adipocytes and at physiological levels, increased uncoupling protein‐1 (UCP‐1) levels in brown adipocytes. These effects of visfatin were similar to that of nicotinamide mononucleotide (NMN), further strengthening the enzymatic role of visfatin. We also showed that leptin induced UCP‐1 mRNA expression and protein production appears to be mediated by visfatin. High concentrations of both visfatin and leptin led to a dramatic decrease in UCP‐1 protein levels, supporting the notion that visfatin levels are raised in obesity and that obese people have reduced BAT activity, plausibly through a reduction in UCP‐1 levels. Additionally, we found differential regulation of key brown adipogenic genes, specifically, PRD1‐BF1‐RIZ1 homologous domain‐containing 16 (PRDM‐16), PPARgamma‐coactivator‐1alpha (PGC‐1&agr;) and receptor‐interacting protein 140 (RIP‐140) by visfatin. Our observations provide novel insights in the potential actions of visfatin in BAT.

Co-localisation analysis of brown adipose deposits on serial 18F-FDG PET/CT scans implies fixed deposits

Purpose: Brown adipose tissue (BAT) is the primary effector organ for non-shivering thermogenesis (NST), which positron emission tomography/computed tomography (PET/CT) studies have shown to be far more prevalent in adult humans than was hitherto believed. Research into weight loss by NST modulation through BAT manipulation requires a reliable imaging biomarker. This study evaluates patterns of BAT uptake on serial PET/CT scans to determine the degree of coincidence over time and the accuracy of PET/CT as a reference standard.