Tapio Viljanen

Different Metabolic Responses of Human Brown Adipose Tissue to Activation by Cold and Insulin

We investigated the metabolism of human brown adipose tissue (BAT) in healthy subjects by determining its cold-induced and insulin-stimulated glucose uptake and blood flow (perfusion) using positron emission tomography (PET) combined with computed tomography (CT). Second, we assessed gene expression in human BAT and white adipose tissue (WAT). Glucose uptake was induced 12-fold in BAT by cold, accompanied by doubling of perfusion. We found a positive association between whole-body energy expenditure and BAT perfusion. Insulin enhanced glucose uptake 5-fold in BAT independently of its perfusion, while the effect on WAT was weaker. The gene expression level of insulin-sensitive glucose transporter GLUT4 was also higher in BAT as compared to WAT. In conclusion, BAT appears to be differently activated by insulin and cold; in response to insulin, BAT displays high glucose uptake without increased perfusion, but when activated by cold, it dissipates energy in a perfusion-dependent manner.

Prospective Analysis of Accuracy of Positron Emission Tomography, Computed Tomography, and Endoscopic Ultrasonography in Staging of Adenocarcinoma of the Esophagus and the Esophagogastric Junction

AbstractBackground: Exact preoperative staging of esophageal cancer is essential for accurate prognosis and selection of appropriate treatment modalities. Methods: Forty-two patients with adenocarcinoma of the esophagus or the esophagogastric junction suitable for radical esophageal resection were staged with positron emission tomography (PET), spiral computed tomography (CT), and endoscopic ultrasonography (EUS). Results: Diagnostic sensitivity for the primary tumor was 83% for PET and 67% for CT; for local peritumoral lymph node metastasis, it was 37% for PET and 89% for EUS; and for distant metastasis, it was 47% for PET and 33% for CT. Diagnostic specificity for local lymph node metastasis was 100% with PET and 54% with EUS, and for distant metastasis, it was 89% for PET and 96% for CT. Accuracy for locoregional lymph node metastasis was 63% for PET, 66% for CT, and 75% for EUS, and for distant metastasis, it was 74% with PET and 74% with CT. Of the 10 patients who were considered inoperable during surgery, PET identified 7 and CT 4. The false-negative diagnoses of stage IV disease in PET were peritoneal carcinomatosis in two patients, abdominal para-aortic cancer growth in one, metastatic lymph nodes by the celiac artery in four, and metastases in the pancreas in one. PET showed false-positive lymph nodes at the jugulum in three patients. Conclusions: The diagnostic value of PET in the staging of adenocarcinoma of the esophagus and the esophagogastric junction is limited because of low accuracy in staging of paratumoral and distant lymph nodes. PET does, however, seem to detect organ metastases better than CT.

Blunted metabolic responses to cold and insulin stimulation in brown adipose tissue of obese humans

Inactive brown adipose tissue (BAT) may predispose to weight gain. This study was designed to measure metabolism in the BAT of obese humans, and to compare it to that in lean subjects. The impact of weight loss on BAT and the association of detectable BAT with various metabolic characteristics were also assessed.

S-ketamine anesthesia increases cerebral blood flow in excess of the metabolic needs in humans.

Background:Animal studies have demonstrated neuroprotective properties of S-ketamine, but its effects on cerebral blood flow (CBF), metabolic rate of oxygen (CMRO2), and glucose metabolic rate (GMR) have not been comprehensively studied in humans. Methods:Positron emission tomography was used to quantify CBF and CMRO2 in eight healthy male volunteers awake and during S-ketamine infusion targeted to subanesthetic (150 ng/ml) and anesthetic (1,500–2,000 ng/ml) concentrations. In addition, subjects’ GMRs were assessed awake and during anesthesia. Whole brain estimates for cerebral blood volume were obtained using kinetic modeling. Results:The mean ± SD serum S-ketamine concentration was 159 ± 21 ng/ml at the subanesthetic and 1,959 ± 442 ng/ml at the anesthetic levels. The total S-ketamine dose was 10.4 mg/kg. S-ketamine increased heart rate (maximally by 43.5%) and mean blood pressure (maximally by 27.0%) in a concentration-dependent manner (P = 0.001 for both). Subanesthetic S-ketamine increased whole brain CBF by 13.7% (P = 0.035). The greatest regional CBF increase was detected in the anterior cingulate (31.6%; P = 0.010). No changes were detected in CMRO2. Anesthetic S-ketamine increased whole brain CBF by 36.4% (P = 0.006) but had no effect on whole brain CMRO2 or GMR. Regionally, CBF was increased in nearly all brain structures studied (greatest increase in the insula 86.5%; P < 0.001), whereas CMRO2 increased only in the frontal cortex (by 15.7%; P = 0.007) and GMR increased only in the thalamus (by 11.7%; P = 0.010). Cerebral blood volume was increased by 51.9% (P = 0.011) during anesthesia. Conclusions:S-ketamine–induced CBF increases exceeded the minor changes in CMRO2 and GMR during anesthesia.

Myocardial and skeletal muscle glucose uptake during exercise in humans

The purpose of this study was to investigate the effects of exercise on myocardial glucose uptake and whether the pattern of glucose uptake is the same as in skeletal muscle. Glucose uptake was measured using positron emission tomography (PET) and 2‐[18F]fluoro‐2‐deoxy‐D‐glucose ([18F]FDG). Twelve healthy men were studied during rest, while 14 subjects were studied after 35 min of bicycle exercise corresponding to 30, 55 and 75 % of maximal oxygen consumption (V̇O2,max) on three separate days. [18F]FDG was injected 10 min after the start of exercise and exercise continued for a further 25 min. Myocardial and skeletal muscle PET scanning was commenced directly after the completion of the exercise bout. As compared to the resting state, exercise doubled myocardial glucose uptake at the 30 % (P= 0.056) and 55 % intensity levels (P < 0.05), while at the 75 % intensity level glucose uptake was reduced significantly compared to the lower exercise intensities. There was no significant difference between the highest intensity level and the resting state (P= 0.18). At rest and during low‐intensity exercise, myocardial glucose uptake was inversely associated with circulating levels of free fatty acids. However, during higher exercise intensities when plasma lactate concentrations increased significantly, this association disappeared. In contrast to myocardial responses, skeletal muscle glucose uptake rose in parallel with exercise intensity from rest to 30 % and then 55 % V̇O2,max (P < 0.001) and tended to increase further at the intensity of 75 % V̇O2,max (P= 0.065). In conclusion, these results demonstrate that myocardial glucose uptake is increased during mild‐ and moderate‐intensity exercise, but is decreased during high‐intensity exercise. This finding suggests that the increased myocardial energy that is needed during high‐intensity exercise is supplied by substrates other than glucose.

Increased Brain Fatty Acid Uptake in Metabolic Syndrome

OBJECTIVE To test whether brain fatty acid uptake is enhanced in obese subjects with metabolic syndrome (MS) and whether weight reduction modifies it. RESEARCH DESIGN AND METHODS We measured brain fatty acid uptake in a group of 23 patients with MS and 7 age-matched healthy control subjects during fasting conditions using positron emission tomography (PET) with [11C]-palmitate and [18F]fluoro-6-thia-heptadecanoic acid ([18F]-FTHA). Sixteen MS subjects were restudied after 6 weeks of very low calorie diet intervention. RESULTS At baseline, brain global fatty acid uptake derived from [18F]-FTHA was 50% higher in patients with MS compared with control subjects. The mean percentage increment was 130% in the white matter, 47% in the gray matter, and uniform across brain regions. In the MS group, the nonoxidized fraction measured using [11C]-palmitate was 86% higher. Brain fatty acid uptake measured with [18F]-FTHA-PET was associated with age, fasting serum insulin, and homeostasis model assessment (HOMA) index. Both total and nonoxidized fractions of fatty acid uptake were associated with BMI. Rapid weight reduction decreased brain fatty acid uptake by 17%. CONCLUSIONS To our knowledge, this is the first study on humans to observe enhanced brain fatty acid uptake in patients with MS. Both fatty acid uptake and accumulation appear to be increased in MS patients and reversed by weight reduction.

Effects of subanesthetic ketamine on regional cerebral glucose metabolism in humans.

Background: The authors have recently shown with positron emission tomography that subanesthetic doses of racemic ket-amine increase cerebral blood flow but do not affect oxygen consumption significantly. In this study, the authors wanted to assess the effects of racemic ketamine on regional glucose metabolic rate (rGMR) in similar conditions to establish whether ketamine truly induces disturbed coupling between cerebral blood flow and metabolism. Methods: 18F-labeled fluorodeoxyglucose was used as a positron emission tomography tracer to quantify rGMR on 12 brain regions of interest of nine healthy male volunteers at baseline and during a 300-ng/ml ketamine target concentration level. In addition, voxel-based analysis was performed for the relative changes in rGMR using statistical parametric mapping. Results: The mean ± SD measured ketamine serum concentration was 326.4 ± 86.3 ng/ml. The mean arterial pressure was slightly increased (maximally by 16.4%) during ketamine infusion (P < 0.001). Ketamine increased absolute rGMR significantly in most regions of interest studied. The greatest increases were detected in the thalamus (14.6 ± 15.9%; P = 0.029) and in the frontal (13.6 ± 13.1%; P = 0.011) and parietal cortices (13.1 ± 11.2%; P = 0.007). Absolute rGMR was not decreased anywhere in the brain. The voxel-based analysis revealed relative rGMR increases in the frontal, temporal, and parietal cortices. Conclusions: Global increases in rGMR seem to parallel ket-amine-induced increases in cerebral blood flow detected in the authors’ earlier study. Therefore, ketamine-induced disturbance of coupling between cerebral blood flow and metabolism is highly unlikely. The previously observed decrease in oxygen extraction fraction may be due to nonoxidative glucose metabolism during ketamine-induced increase in glutamate release.

Increased physical activity decreases hepatic free fatty acid uptake : a study in human monozygotic twins

Exercise is considered to be beneficial for free fatty acid (FFA) metabolism, although reports of the effects of increased physical activity on FFA uptake and oxidation in different tissues in vivo in humans have been inconsistent. To investigate the heredity‐independent effects of physical activity and fitness on FFA uptake in skeletal muscle, the myocardium, and liver we used positron emission tomography (PET) in nine healthy young male monozygotic twin pairs discordant for physical activity and fitness. The cotwins with higher physical activity constituting the more active group had a similar body mass index but less body fat and 18 ± 10% higher (P < 0.001) compared to the less active brothers with lower physical activity. Low‐intensity knee‐extension exercise increased skeletal muscle FFA and oxygen uptake six to 10 times compared to resting values but no differences were observed between the groups at rest or during exercise. At rest the more active group had lower hepatic FFA uptake compared to the less active group (5.5 ± 4.3 versus 9.0 ± 6.1 μmol (100 ml)−1 min−1, P= 0.04). Hepatic FFA uptake associated significantly with body fat percentage (P= 0.05). Myocardial FFA uptake was similar between the groups. In conclusion, in the absence of the confounding effects of genetic factors, moderately increased physical activity and aerobic fitness decrease body adiposity even in normal‐weighted healthy young adult men. Further, increased physical activity together with decreased intra‐abdominal adiposity seems to decrease hepatic FFA uptake but has no effects on skeletal muscle or myocardial FFA uptake.

Amyloid and metabolic positron emission tomography imaging of cognitively normal adults with Alzheimer's parents.

This study examines the relationship between fibrillar beta-amyloid (Aβ) deposition and reduced glucose metabolism, a proxy for neuronal dysfunction, in cognitively normal (NL) individuals with a parent affected by late-onset Alzheimers disease (AD). Forty-seven 40-80-year-old NL received positron emission tomography (PET) with (11)C-Pittsburgh compound B (PiB) and 18F-fluoro-2-deoxy-d-glucose (FDG). These included 19 NL with a maternal history (MH), 12 NL with a paternal history (PH), and 16 NL with negative family history of AD (NH). Automated regions of interest, statistical parametric mapping, voxel-wise intermodality correlations, and logistic regressions were used to examine cerebral-to-cerebellar PiB and FDG standardized uptake value ratios across groups. The MH group showed higher PiB retention and lower metabolism in AD regions compared with NH and PH, which were negatively correlated in posterior cingulate, frontal, and parieto-temporal regions (Pearson r ≤ -0.57, p ≤ 0.05). No correlations were observed in NH and PH. The combination of Aβ deposition and metabolism yielded accuracy ≥ 69% for MH vs. NH and ≥ 71% for MH vs. PH, with relative risk = 1.9-5.1 (p values < 0.005). NL individuals with AD-affected mothers show co-occurring Aβ increases and hypometabolism in AD-vulnerable regions, suggesting an increased risk for AD.

Muscle use during double poling evaluated by positron emission tomography

Due to the complexity of movement in cross-country skiing (XCS), the muscle activation patterns are not well elucidated. Previous studies have applied surface electromyography (SEMG); however, recent gains in three-dimensional (3D) imaging techniques such as positron emission tomography (PET) have rendered an alternative approach to investigate muscle activation. The purpose of the present study was to examine muscle use during double poling (DP) at two work intensities by use of PET. Eight male subjects performed two 20-min DP bouts on separate days. Work intensity was ∼ 53 and 74% of peak oxygen uptake (Vo(2peak)), respectively. During exercise 188 ± 8 MBq of [(18)F]fluorodeoxyglucose ([(18)F]FDG) was injected, and subsequent to exercise a full-body PET scan was conducted. Regions of interest (ROI) were defined within 15 relevant muscles, and a glucose uptake index (GUI) was determined for all ROIs. The muscles that span the shoulder and elbow joints, the abdominal muscles, and hip flexors displayed the greatest GUI during DP. Glucose uptake did not increase significantly from low to high intensity in most upper body muscles; however, an increased GUI (P < 0.05) was seen for the knee flexor (27%) and extensor muscles (16%), and for abdominal muscles (21%). The present data confirm previous findings that muscles of the upper limb are the primary working muscles in DP. The present data further suggest that when exercise intensity increases, the muscles that span the lumbar spine, hip, and knee joints contribute increasingly. Finally, PET provides a promising alternative or supplement to existing methods to assess muscle activation in complex human movements.