Boudewijn Brans

Brown adipose tissue in morbidly obese subjects.

Background Cold-stimulated adaptive thermogenesis in brown adipose tissue (BAT) to increase energy expenditure is suggested as a possible therapeutic target for the treatment of obesity. We have recently shown high prevalence of BAT in adult humans, which was inversely related to body mass index (BMI) and body fat percentage (BF%), suggesting that obesity is associated with lower BAT activity. Here, we examined BAT activity in morbidly obese subjects and its role in cold-induced thermogenesis (CIT) after applying a personalized cooling protocol. We hypothesize that morbidly obese subjects show reduced BAT activity upon cold exposure. Methods and Findings After applying a personalized cooling protocol for maximal non-shivering conditions, BAT activity was determined using positron-emission tomography and computed tomography (PET-CT). Cold-induced BAT activity was detected in three out of 15 morbidly obese subjects. Combined with results from lean to morbidly obese subjects (n = 39) from previous study, the collective data show a highly significant correlation between BAT activity and body composition (P<0.001), respectively explaining 64% and 60% of the variance in BMI (r = 0.8; P<0.001) and BF% (r = 0.75; P<0.001). Obese individuals demonstrate a blunted CIT combined with low BAT activity. Only in BAT-positive subjects (n = 26) mean energy expenditure was increased significantly upon cold exposure (51.5±6.7 J/s versus 44.0±5.1 J/s, P = 0.001), and the increase was significantly higher compared to BAT-negative subjects (+15.5±8.9% versus +3.6±8.9%, P = 0.001), indicating a role for BAT in CIT in humans. Conclusions This study shows that in an extremely large range of body compositions, BAT activity is highly correlated with BMI and BF%. BAT-positive subjects showed higher CIT, indicating that BAT is also in humans involved in adaptive thermogenesis. Increasing BAT activity could be a therapeutic target in (morbid) obesity.

Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus

Cold exposure may be a potential therapy for diabetes by increasing brown adipose tissue (BAT) mass and activity. Here we report that 10 d of cold acclimation (14–15 °C) increased peripheral insulin sensitivity by ∼43% in eight type 2 diabetes subjects. Basal skeletal muscle GLUT4 translocation markedly increased, without effects on insulin signaling or AMP-activated protein kinase (AMPK) activation and only a minor increase in BAT glucose uptake.

Increase in Brown Adipose Tissue Activity after Weight Loss in Morbidly Obese Subjects

CONTEXT Stimulation of thermogenesis in brown adipose tissue (BAT) is a potential target to treat obesity. We earlier demonstrated that BAT activity is relatively low in obese subjects. It is unknown whether BAT can be recruited in adult humans. OBJECTIVE To study the dynamics of BAT, we observed BAT activity in morbidly obese subjects before and after weight loss induced by bariatric surgery. DESIGN This was an observational prospective cohort study. SETTING The study was conducted at a referral center. PATIENTS Ten morbidly obese subjects eligible for laparoscopic adjustable gastric banding surgery were studied before and 1 yr after bariatric surgery. MAIN OUTCOME MEASURE The main outcome measure was BAT activity, as determined after acute cold stimulation using (18)F-fluorodeoxyglucose positron emission tomography and computed tomography. RESULTS Before surgery, only two of 10 subjects showed active BAT. One year after surgery, the number of subjects with active BAT was increased to five. After weight loss, BAT-positive subjects had significantly higher nonshivering thermogenesis compared with BAT-negative subjects (P < 0.05). CONCLUSIONS The results show that in humans BAT can be recruited in the regions in which it was also reported in lean subjects before. These results for the first time show recruitment of BAT in humans and may open the door for BAT-targeted treatments of obesity.

Systemic β-Adrenergic Stimulation of Thermogenesis Is Not Accompanied by Brown Adipose Tissue Activity in Humans

Brown adipose tissue (BAT) is currently considered as a target to combat obesity and diabetes in humans. BAT is densely innervated by the sympathetic nervous system (SNS) and can be stimulated by β-adrenergic agonists, at least in animals. However, the exact role of the β-adrenergic part of the SNS in BAT activation in humans is not known yet. In this study, we measured BAT activity by 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) positron emission tomography/computed tomography imaging in 10 lean men during systemic infusion of the nonselective β-agonist isoprenaline (ISO) and compared this with cold-activated BAT activity. ISO successfully mimicked sympathetic stimulation as shown by increased cardiovascular and metabolic activity. Energy expenditure increased to similar levels as during cold exposure. Surprisingly, BAT was not activated during β-adrenergic stimulation. We next examined whether the high plasma free fatty acid (FFA) levels induced by ISO competed with glucose ([18F]FDG) uptake in BAT locations by blocking lipolysis with acipimox (ACI). ACI successfully lowered plasma FFA, but did not increase [18F]FDG-uptake in BAT. We therefore conclude that systemic nonselective β-adrenergic stimulation by ISO at concentrations that increase energy expenditure to the same extent as cold exposure does not activate BAT in humans, indicating that other tissues are responsible for the increased β-adrenergic thermogenesis.

The Bile Acid Chenodeoxycholic Acid Increases Human Brown Adipose Tissue Activity

The interest in brown adipose tissue (BAT) as a target to combat metabolic disease has recently been renewed with the discovery of functional BAT in humans. In rodents, BAT can be activated by bile acids, which activate type 2 iodothyronine deiodinase (D2) in BAT via the G-coupled protein receptor TGR5, resulting in increased oxygen consumption and energy expenditure. Here we examined the effects of oral supplementation of the bile acid chenodeoxycholic acid (CDCA) on human BAT activity. Treatment of 12 healthy female subjects with CDCA for 2 days resulted in increased BAT activity. Whole-body energy expenditure was also increased upon CDCA treatment. In vitro treatment of primary human brown adipocytes derived with CDCA or specific TGR5 agonists increased mitochondrial uncoupling and D2 expression, an effect that was absent in human primary white adipocytes. These findings identify bile acids as a target to activate BAT in humans.

Brown adipose tissue activity after a high-calorie meal in humans

BACKGROUND Studies in rodents have shown that brown adipose tissue (BAT) is activated on food intake, thereby reducing metabolic efficiency. OBJECTIVE The current study investigated whether a single high-calorie, carbohydrate-rich meal activates BAT in lean human adults. DESIGN BAT activity was studied in 11 lean adult men [age: 23.6 ± 2.1 y; body mass index (BMI; in kg/m(2)): 22.4 ± 2.1] after consumption of a high-calorie, carbohydrate-rich meal (1622 ± 222 kcal; 78% carbohydrate, 12% protein, 10% fat). BAT activity during 2 h of mild cold exposure served as a positive control experiment. BAT activity was assessed by [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography-computed tomography. Energy expenditure was measured by indirect calorimetry. RESULTS Postprandial [(18)F]FDG uptake was significantly higher in BAT [1.65 ± 0.99 mean standard uptake value (SUVmean)] than in subcutaneous (0.35 ± 0.15 SUVmean; P < 0.05) and visceral (0.49 ± 0.24 SUVmean; P < 0.05) white adipose tissue and liver (0.95 ± 0.28 SUVmean; P < 0.05). Postprandial BAT activity was lower than cold-induced BAT activity (7.19 ± 2.09 SUVmean). However, postprandial BAT activity may have been underestimated because of high postprandial [(18)F]FDG uptake in skeletal muscle compared with cold (1.36 ± 0.31 compared with 0.59 ± 0.07 SUVmean, P < 0.05), which reduces [(18)F]FDG bioavailability for BAT and other tissues. No direct relation was found between BAT and diet-induced thermogenesis (DIT). CONCLUSIONS Glucose uptake in BAT increases after a meal in humans, which indicates a role for BAT in reducing metabolic efficiency. However, the quantitative contribution of BAT to DIT relative to other tissues, such as skeletal muscle, remains to be investigated. This trial was registered at www.controlled-trials.com as ISRCTN21413505.

SPECT neuropsychological activation procedure with the Verbal Fluency Test in attempted suicide patients

Performance on the Verbal Fluency Test, as a measure of the ability of initiating processes, is reduced in depressed suicidal patients. The hampered results in this prefrontal executive task parallel the reduction in prefrontal blood perfusion and metabolism in depressed subjects. A neuropsychological activation study with the verbal fluency paradigm could evaluate a possible blunted increase in perfusion in the prefrontal cortex in depressed suicidal patients. Twenty clinically depressed patients who had recently attempted suicide and 20 healthy volunteers were included in a single photon emission computed tomography (SPECT) split-dose activation study following a verbal fluency paradigm. Statistical parametric mapping was used to determine voxelwise significant changes. Differences in regional cortical activation between the letter fluency and category fluency tasks in attempted suicide patients were found. These patients showed a blunted increase in perfusion in the prefrontal cortex. Methodological restrictions concerning group uniformity, medication bias and subjective effort of the participants are discussed. Our findings indicate a blunted increase in prefrontal blood perfusion as a possible biological reason for reduced drive and loss of initiative in attempted suicide patients.

Clinical radionuclide therapy dosimetry: the quest for the "Holy Gray".

IntroductionRadionuclide therapy has distinct similarities to, but also profound differences from external radiotherapy.ReviewThis review discusses techniques and results of previously developed dosimetry methods in thyroid carcinoma, neuro-endocrine tumours, solid tumours and lymphoma. In each case, emphasis is placed on the level of evidence and practical applicability. Although dosimetry has been of enormous value in the preclinical phase of radiopharmaceutical development, its clinical use to optimise administered activity on an individual patient basis has been less evident. In phase I and II trials, dosimetry may be considered an inherent part of therapy to establish the maximum tolerated dose and dose-response relationship. To prove that dosimetry-based radionuclide therapy is of additional benefit over fixed dosing or dosing per kilogram body weight, prospective randomised phase III trials with appropriate end points have to be undertaken. Data in the literature which underscore the potential of dosimetry to avoid under- and overdosing and to standardise radionuclide therapy methods internationally are very scarce.DevelopmentsIn each section, particular developments and insights into these therapies are related to opportunities for dosimetry. The recent developments in PET and PET/CT imaging, including micro-devices for animal research, and molecular medicine provide major challenges for innovative therapy and dosimetry techniques. Furthermore, the increasing scientific interest in the radiobiological features specific to radionuclide therapy will advance our ability to administer this treatment modality optimally.

Acute single photon emission computed tomographic study of vagus nerve stimulation in refractory epilepsy

Summary: Purpose: Left‐sided vagus nerve stimulation (VNS) is an efficacious treatment for patients with refractory epilepsy. The precise mechanism of action remains to be elucidated. Only limited data on VNS‐induced changes in regional cerebral blood flow (rCBF) are available. The aim of this study was to investigate rCBF changes during initial VNS with single‐photon emission computed tomography (SPECT).

EANM procedure guideline for the treatment of liver cancer and liver metastases with intra-arterial radioactive compounds

Primary liver cancers (i.e. hepatocellular carcinoma or cholangiocarcinoma) are worldwide some of the most frequent cancers, with rapidly fatal liver failure in a large majority of patients. Curative therapy consists of surgery (i.e. resection or liver transplantation), but only 10–20% of patients are candidates for this. In other patients, a variety of palliative treatments can be given, such as chemoembolization, radiofrequency ablation or recently introduced tyrosine kinase inhibitors, e.g. sorafenib. Colorectal cancer is the second most lethal cancer in Europe and liver metastases are prevalent either at diagnosis or in follow-up. These patients are usually treated by a sequence of surgery, chemotherapy and antibody therapy [Okuda et al. (Cancer 56:918–928, 1985); Schafer and Sorrell (Lancet 353:1253–1257, 1999); Leong et al. (Arnold, London, 1999)]. Radioembolization is an innovative therapeutic approach defined as the injection of micron-sized embolic particles loaded with a radioisotope by use of percutaneous intra-arterial techniques. Advantages of the use of these intra-arterial radioactive compounds are the ability to deliver high doses of radiation to small target volumes, the relatively low toxicity profile, the possibility to treat the whole liver including microscopic disease and the feasibility of combination with other therapy modalities. Disadvantages are mainly due to radioprotection constraints mainly for 131I-labelled agents, logistics and the possibility of inadvertent delivery or shunting [Novell et al. (Br J Surg 78:901–906, 1991)]. The Therapy, Oncology and Dosimetry Committees have worked together in order to revise the European Association of Nuclear Medicine (EANM) guidelines on the use of the radiopharmaceutical 131I-Lipiodol (Lipiocis®, IBA, Brussels, Belgium) and include the newer medical devices with 90Y-microspheres. 90Y is either bound to resin (SIR-Spheres®, Sirtex Medical, Lane Cove, Australia) or embedded in a glass matrix (TheraSphere®, MDS Nordion, Kanata, ON, Canada). Since 90Y-microspheres are not metabolized, they are not registered as unsealed sources. However, the microspheres are delivered in aqueous solution: radioactive contamination is a concern and microspheres should be handled, like other radiopharmaceuticals, as open sources. The purpose of this guideline is to assist the nuclear medicine physician in treating and managing patients undergoing such treatment.