Antti Viljanen

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.

Contribution of Glucose Tolerance and Gender to Cardiac Adiposity

CONTEXT AND OBJECTIVE To examine whether pericardial and myocardial fat depots may contribute to the association between diabetes and cardiovascular risk, including sex-related differences, and the role of adiponectin, we evaluated data in patients with obesity and without diabetes [nondiabetic (ND)] or with impaired glucose tolerance or type 2 diabetes and in lean ND controls. METHODS Magnetic resonance imaging and spectroscopy were used to measure left ventricular (LV) function and abdominal sc and visceral fat areas to estimate respective masses, pericardial fat depots, and myocardial triglyceride content in 53 subjects (10 lean ND, 25 obese ND, six impaired-glucose-tolerance, and 12 type 2 diabetic patients with macrovascular disease); gender effects and adiponectin levels were evaluated in the available subset of subjects. RESULTS Myocardial and pericardial fat increased progressively across study groups. They were lower in obese women than men (P = 0.002), but cardiac steatosis caught up in hyperglycemic women (+81% vs. ND, P = 0.01). Adiponectin was inversely related with both fat depots (P < 0.01) and LV mass (P = 0.003) and positively with LV function (P = 0.03). In multiple regression analysis, myocardial and pericardial fat were independently related with plasma glucose levels, only pericardial fat mass was associated with visceral adiposity and myocardial fat with cardiac output and work. CONCLUSIONS We conclude that glycemia, gender, adiponectin, and cardiac workload are associated with, and hyperglycemia and male gender are independent positive predictors of, heart adiposity. Once glucose tolerance becomes impaired, the evolution of cardiac steatosis is more pronounced in women.

Effect of Weight Loss on Liver Free Fatty Acid Uptake and Hepatic Insulin Resistance

OBJECTIVE Weight loss has been shown to decrease liver fat content and whole-body insulin resistance. The current study was conducted to investigate the simultaneous effects of rapid weight reduction with a very-low-calorie diet on liver glucose and fatty acid metabolism and liver adiposity. HYPOTHESIS We hypothesized that liver insulin resistance and free fatty acid uptake would decrease after weight loss and that they are associated with reduction of liver fat content. DESIGN Thirty-four healthy obese subjects (body mass index, 33.7 +/- 8.0 kg/m(2)) were studied before and after a very-low-calorie diet for 6 wk. Hepatic glucose uptake and endogenous glucose production were measured with [(18)F]fluorodeoxyglucose during hyperinsulinemic euglycemia and fasting hepatic fatty acid uptake with [(18)F]fluoro-6-thia-heptadecanoic acid and positron emission tomography. Liver volume and fat content were measured using magnetic resonance imaging and spectroscopy. RESULTS Subjects lost weight (11.2 +/- 2.9 kg; P < 0.0001). Liver volume decreased by 11% (P < 0.002), which was partly explained by decreased liver fat content (P < 0.0001). Liver free fatty acid uptake was 26% lower after weight loss (P < 0.003) and correlated with the decrement in liver fat content (r = 0.54; P < 0.03). Hepatic glucose uptake during insulin stimulation was unchanged, but the endogenous glucose production decreased by 40% (P < 0.04), and hepatic insulin resistance by 40% (P < 0.05). CONCLUSIONS The liver responds to a 6-wk period of calorie restriction with a parallel reduction in lipid uptake and storage, accompanied by enhancement of hepatic insulin sensitivity and clearance.

Effect of Caloric Restriction on Myocardial Fatty Acid Uptake, Left Ventricular Mass, and Cardiac Work in Obese Adults

Obesity is associated with increased fatty acid uptake in the myocardium, and this may have deleterious effects on cardiac function. The aim of this study was to evaluate how weight loss influences myocardial metabolism and cardiac work in obese adults. Thirty-four obese (mean body mass index 33.7 +/- 0.7 kg/m(2)) but otherwise healthy subjects consumed a very low calorie diet for 6 weeks. Cardiac substrate metabolism and work were measured before and after the diet. Myocardial fatty acid uptake was measured in 18 subjects using fluorine-18-fluoro-6-thia-heptadecanoic acid and positron emission tomography, and myocardial glucose uptake was measured in 16 subjects using fluorine-18-2-fluoro-2-deoxyglucose. Myocardial structure and cardiac function were measured using magnetic resonance imaging. Consumption of the very low calorie diet decreased weight (-11.2 +/- 0.6 kg, p <0.0001). Myocardial fatty acid uptake decreased from 4.2 +/- 0.4 to 2.9 +/- 0.2 micromol/100 g/min (p <0.0001). Myocardial mass decreased by 7% (p <0.005), and cardiac work decreased by 26% (p <0.0001). Whole-body insulin sensitivity increased by 33% (p <0.01), but insulin-stimulated myocardial glucose uptake remained unchanged (p = 0.90). Myocardial triglyceride content decreased by 31% (n = 8, p = 0.076). In conclusion, weight reduction decreases myocardial fatty acid uptake in parallel with myocardial mass and cardiac work. These results show that the increased fatty acid uptake found in the hearts of obese patients can be reversed by weight loss.

Effects of weight loss on visceral and abdominal subcutaneous adipose tissue blood-flow and insulin-mediated glucose uptake in healthy obese subjects.

Objective. Rapid weight loss with very-low-calorie diet (VLCD) is known to improve insulin sensitivity and decrease adipose tissue masses. The aim was to investigate the effects of VLCD on adipose tissue regional glucose uptake (rGU) and perfusion and their association with adipokines. Research design and methods. Sixteen healthy obese (body mass index 33±1.1 kg/m2) subjects underwent VLCD for 6 weeks. RGU and perfusion were measured using [18F]-fluoro-deoxy-glucose, [15O]H2O and positron emission tomography. Results. Blood-flow and rGU expressed per gram of adipose tissue were higher in visceral fat compared to abdominal subcutaneous fat (P<0.01 for both). Dieting decreased weight by 11±0.9 kg (P<0.0001). Visceral adipose fat decreased by 25% (P<0.001) and abdominal subcutaneous fat by 16% (P<0.001). Whole body insulin sensitivity increased by 33% (P<0.01). Perfusion of both fat depots decreased (P<0.001), while rGU remained unchanged. Among the adipokines, leptin and interleukin-6 levels seemed to be associated with abdominal subcutaneous and intra-abdominal adipose tissue insulin resistance but not with adipose tissue perfusion. Conclusions. Abdominal adipose tissue perfusion and rGU are not related in obesity. Rapid weight loss decreases perfusion through adipose tissue depots but has no influence on rGU demonstrating the ‘sink’ role of adipose tissue.

Higher Free Fatty Acid Uptake in Visceral Than in Abdominal Subcutaneous Fat Tissue in Men

Visceral adipose tissue has been shown to have high lipolytic activity. The aim of this study was to examine whether free fatty acid (FFA) uptake into visceral adipose tissue is enhanced compared to abdominal subcutaneous tissue in vivo. Abdominal adipose tissue FFA uptake was measured using positron emission tomography (PET) and [18F]‐labeled 6‐thia‐hepta‐decanoic acid ([18F]FTHA) and fat masses using magnetic resonance imaging (MRI) in 18 healthy young adult males. We found that FFA uptake was 30% higher in visceral compared to subcutaneous adipose tissue (0.0025 ± 0.0018 vs. 0.0020 ± 0.0016 µmol/g/min, P = 0.005). Visceral and subcutaneous adipose tissue FFA uptakes were strongly associated with each other (P < 0.001). When tissue FFA uptake per gram of fat was multiplied by the total tissue mass, total FFA uptake was almost 1.5 times higher in abdominal subcutaneous than in visceral adipose tissue. In conclusion, we observed enhanced FFA uptake in visceral compared to abdominal subcutaneous adipose tissue and, simultaneously, these metabolic rates were strongly associated with each other. The higher total tissue FFA uptake in subcutaneous than in visceral adipose tissue indicates that although visceral fat is active in extracting FFA, its overall contribution to systemic metabolism is limited in healthy lean males. Our results indicate that subcutaneous, rather than visceral fat storage plays a more direct role in systemic FFA availability. The recognized relationship between abdominal visceral fat mass and metabolic complications may be explained by direct effects of visceral fat on the liver.

The interaction of blood flow, insulin, and bradykinin in regulating glucose uptake in lower-body adipose tissue in lean and obese subjects.

CONTEXT Impaired adipose tissue (AT) blood flow has been implicated in the pathogenesis of insulin resistance in obesity. Insulin and bradykinin are meal-stimulated promoters of AT blood flow and glucose metabolism. OBJECTIVE We tested whether blood flow regulates glucose metabolism in AT, insulin and bradykinin exert additive effects on AT blood flow and metabolism, and any of these actions explains the insulin resistance observed in obese individuals. DESIGN Perfusion and glucose metabolism in the AT of the thighs were studied by positron emission tomography and H(2)(15)O (flow tracer) and (18)F-2-fluoro-2-deoxyglucose. Study I included five subjects in whom positron emission tomography imaging was performed in the fasting state during intraarterial infusion of bradykinin in the left leg; the right leg served as a control. Study II included seven lean and eight obese subjects in whom the imaging protocol was performed during euglycemic hyperinsulinemia. RESULTS Bradykinin alone doubled fasting AT blood flow without modifying glucose uptake. Hyperinsulinemia increased AT blood flow (P ≤ 0.05) similarly in lean and obese individuals. In the lean group, bradykinin increased insulin-mediated AT glucose uptake from 8.6 ± 1.6 to 12.3 ± 2.4 μmol/min · kg (P = 0.038). In the obese group, AT glucose uptake was impaired (5.0 ± 1.0 μmol/min · kg, P = 0.05 vs. the lean group), and bradykinin did not exert any metabolic action (6.0 ± 0.8 μmol/min · kg, P = 0.01 vs. the lean group). CONCLUSION AT blood flow is not an independent regulator of AT glucose metabolism. Insulin is a potent stimulator of AT blood flow, and bradykinin potentiates the hemodynamic and metabolic actions of insulin in lean but not in obese individuals.

Quantification of liver perfusion with [15O]H2O-PET and its relationship with glucose metabolism and substrate levels

BACKGROUND/AIMS Hepatic perfusion plays an important role in liver physiology and disease. This study was undertaken to (a) validate the use of Positron Emission Tomography (PET) and oxygen-15-labeled water ([(15)O]H(2)O) to quantify hepatic and portal perfusion, and (b) examine relationships between portal perfusion and liver glucose and lipid metabolism. METHODS Liver [(15)O]H(2)O-PET images were obtained in 14 pigs during fasting or hyperinsulinemia. Carotid arterial and portal venous blood were sampled for [(15)O]H(2)O activity; Doppler ultrasonography was used invasively as the reference method. A single arterial input compartment model was developed to estimate portal tracer kinetics and liver perfusion. Endogenous glucose production (EGP) and insulin-mediated whole body glucose uptake (wbGU) were determined by standard methods. RESULTS Hepatic arterial and portal venous perfusions were 0.15+/-0.07 and 1.11+/-0.34 ml/min/ml of tissue, respectively. The agreement between ultrasonography and [(15)O]H(2)O-PET was good for total and portal liver perfusion, and poor for arterial perfusion. Portal perfusion was correlated with EGP (r=or+0.62, p=0.03), triglyceride (r=or+0.66, p=0.01), free fatty acid levels (r=or+0.76, p=0.003), and plasma lactate levels (r=or-0.81, p=0.0009). CONCLUSIONS Estimates of liver perfusion by [(15)O]H(2)O-PET compared well with those by ultrasonography. The method allowed to predict portal tracer concentrations which is essential in human studies. Portal perfusion may affect liver nutrient handling.

The Pro12Ala polymorphism of the PPARγ2 gene is associated with hepatic glucose uptake during hyperinsulinemia in subjects with type 2 diabetes mellitus

The Ala12 allele of the peroxisome proliferator-activated receptor gamma gene (PPARG2) has been associated with reduced risk of type 2 diabetes mellitus (T2DM) and increased whole-body and skeletal muscle insulin sensitivity in nondiabetic subjects. The effect of the Pro12Ala polymorphism on tissue specific insulin sensitivity in subjects with T2DM has not been previously investigated. We studied the effect of the Pro12Ala polymorphism on the rates of whole-body, skeletal muscle, and subcutaneous adipose tissue glucose uptake (GU) in T2DM subjects, and the rates of hepatic GU in nondiabetic and T2DM subjects during hyperinsulinemia. Our study included 105 T2DM subjects whose whole-body, skeletal muscle, subcutaneous adipose tissue, and hepatic GUs were measured using (18)F-fluorodeoxyglucose and positron emission tomography during the hyperinsulinemic euglycemic clamp. Hepatic GU was also measured in 68 nondiabetic subjects. In obese (body mass index >or=27 kg/m(2)) subjects with T2DM, the rate of hepatic GU was 28% lower in subjects with the Pro12Pro genotype than in carriers of the Ala12 allele (P = .001); and a similar trend was observed in nondiabetic obese subjects (P = .137). No effect of the Pro12Ala polymorphism on the rates of whole-body, skeletal muscle, or subcutaneous adipose tissue GU was observed in T2DM subjects. We conclude that the Ala12 allele of PPARG2 is associated with higher hepatic GU in obese subjects with T2DM.

Non-Invasive Estimation of Subcutaneous and Visceral Adipose Tissue Blood Flow by Using [15O]H2O PET with Image Derived Input Functions

Subcutaneous adipose tissue blood flow is finely regulated, and tuned with fat metabolism; little is known about visceral fat, which is less accessible in humans. In estimating blood flow with positron emission tomography (PET) and oxygen-15-labelled water (( 15 O)H2O), the input function is obtained invasively from arterial blood samples. The aim of the current study was to validate a non-invasive method to measure blood flow in adipose depots, by extracting input function curves from ( 15 O)H2O-PET images. Data of twenty subjects undergoing abdominal ( 15 O)H2O-PET were used. Images were reconstructed with filtered backprojection (FBP). Location, diameter, and inner radioactivity levels of the abdominal aorta were automatically determined. Image derived arterial curves (IDI) were compared to measured arterial blood data, as obtained by an online blood sampler (OSI). Blood flow in three adipose tissue depots was estimated using the autoradiographic method with OSI vs the FBP image derived input (F-IDI) function. Correlations between blood flow results obtained with OSI and IDI were significant (r 0.87, p<0.0001) in all regions. Estimates of the aortic diameter ranged between 10.7-17.2 mm. A good agreement was found between area under the curve (AUC) values of F-IDI and OSI curves; the AUCF-IDI/AUCOSI ratio was 0.97±0.10. Our results support the implementation of the current method for the non-invasive detection of the abdominal aorta input function from a dynamic ( 15 O)H2O PET image in the quantifica- tion of regional blood flow in low flow tissues. This method allows simultaneously examine subcutaneous and intra- abdominal fat depots.