Postprandial Oxidative Metabolism of Human Brown Fat Indicates Thermogenesis.

Human studies suggest that a meal elevates glucose uptake in brown adipose tissue (BAT). However, in postprandial state the thermogenic activity and the metabolism of non-esterified fatty acids (NEFAs) in BAT remain unclear. Using indirect calorimetry combined with positron emission tomography and computed tomography (PET/CT), we showed that whole-body and BAT thermogenesis (oxygen consumption) increases after the ingestion of a mixed carbohydrate-rich meal, to the same extent as in cold stress. Postprandial NEFA uptake into BAT is minimal, possibly due to elevated plasma insulin inhibiting lipolysis. However, the variation in postprandial NEFA uptake is linked to BAT thermogenesis. We identified several genes participating in lipid metabolism to be expressed at higher levels in BAT compared with white fat in postprandial state, and to be positively correlated with BAT UCP1 expression. These findings suggest that substrates preferred by BAT in postprandial state are glucose or LPL-released NEFAs due to insulin stimulation.

Human Brown Fat Radiodensity Indicates Underlying Tissue Composition and Systemic Metabolic Health.

Context: Metabolic imaging studying brown adipose tissue (BAT) physiology has increased, in which computed tomography (CT) is commonly used as an anatomical reference for metabolic positron emission tomography (PET) imaging. However, the capacity of CT to provide metabolic information has been underexploited. Objective: To evaluate whether CT radiodensity of BAT could noninvasively estimate underlying tissue morphology, regarding amount of stored triglycerides. Furthermore, could the alteration in tissue characteristics due to cold stimulus, as a marker for active BAT, be detected with radiodensity? Can BAT be differentiated from white adipose tissue (WAT) solely using CT-based measurements? Design, Setting, and Participants: A cross-sectional study evaluating 66 healthy human subjects with CT, PET, and 1H-magnetic resonance spectroscopy (1H-MRS). Main Outcome Measures: BAT radiodensity was measured with CT. BAT-stored triglyceride content was measured with 1H-MRS. Arterial blood volume in BAT, as a marker of tissue vascularity, was measured with [15O]H2O, along with glucose or fatty acid uptake using [18F]2-fluoro-2-deoxy-D-glucose or 14(R,S)-[18F]fluoro-6-thia-heptadecanoic acid PET imaging, respectively. Results: BAT radiodensity was found to be correlating with tissue-retained blood and triglyceride content. Cold stimulus induced an increase in BAT radiodensity. Active BAT depots had higher radiodensity than both nonactive BAT and WAT. BAT radiodensity associated with systemic metabolic health parameters. Conclusion: BAT radiodensity can be used as a marker of underlying tissue morphology. Active BAT can be identified using CT, exploiting tissue composition information. Moreover, BAT radiodensity provides an insight into whole-body systemic metabolic health.

Human brown adipose tissue [(15)O]O2 PET imaging in the presence and absence of cold stimulus.

PURPOSE: Brown adipose tissue (BAT) is considered a potential target for combatting obesity, as it produces heat instead of ATP in cellular respiration due to uncoupling protein-1 (UCP-1) in mitochondria. However, BAT-specific thermogenic capacity, in comparison to whole-body thermogenesis during cold stimulus, is still controversial. In our present study, we aimed to determine human BAT oxygen consumption with [(15)O]O2 positron emission tomography (PET) imaging. Further, we explored whether BAT-specific energy expenditure (EE) is associated with BAT blood flow, non-esterified fatty acid (NEFA) uptake, and whole-body EE. METHODS: Seven healthy study subjects were studied at two different scanning sessions, 1) at room temperature (RT) and 2) with acute cold exposure. Radiotracers [(15)O]O2, [(15)O]H2O, and [(18)F]FTHA were given for the measurements of BAT oxygen consumption, blood flow, and NEFA uptake, respectively, with PET-CT. Indirect calorimetry was performed to assess differences in whole-body EE between RT and cold. RESULTS: BAT-specific EE and oxygen consumption was higher during cold stimulus (approx. 50 %); similarly, whole-body EE was higher during cold stimulus (range 2-47 %). However, there was no association in BAT-specific EE and whole-body EE. BAT-specific EE was found to be a minor contributor in cold induced whole-body thermogenesis (almost 1 % of total whole-body elevation in EE). Certain deep muscles in the cervico-thoracic region made a major contribution to this cold-induced thermogenesis (CIT) without any visual signs or individual perception of shivering. Moreover, BAT-specific EE associated with BAT blood flow and NEFA uptake both at RT and during cold stimulus. CONCLUSION: Our study suggests that BAT is a minor and deep muscles are a major contributor to CIT. In BAT, both in RT and during cold, cellular respiration is linked with circulatory NEFA uptake.

The effects of bariatric surgery on pancreatic lipid metabolism and blood flow.

CONTEXT: Bariatric surgery leads to a rapid and sustained weight loss often accompanied with improvement in glucose homeostasis. OBJECTIVE: The objective of this study was to investigate the effects of bariatric surgery on pancreatic lipid metabolism, blood flow, and glycemic control. DESIGN: This was a longitudinal study. SETTING: The study was conducted in a clinical research center. PARTICIPANTS: This study included 27 morbidly obese and 15 healthy control subjects. INTERVENTIONS: Measurements were performed using positron emission tomography with the palmitate analog 14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid and radiowater ([(15)O]H2O) and computed tomography. In morbidly obese subjects, positron emission tomography/computed tomography imaging studies were performed before and 6 months after bariatric surgery (either Roux-en-Y gastric bypass or sleeve gastrectomy). MAIN OUTCOME MEASURES: Pancreatic fat and fat-free volume, fatty acid uptake and blood flow were measured as well as parameters of ß-cell function, glucose tolerance, and insulin sensitivity. RESULTS: Six months after bariatric surgery, 23% excess weight loss was observed (P < .0001), and diabetes remission was seen in 7 of 10 patients. When compared with preoperative values, after surgery, notable decreases in pancreatic fat volume (P < .01), fatty acid uptake, and blood flow (both P < .05) were seen, whereas no change was seen in pancreatic fat-free volume. The decrease in pancreatic fat volume and the preservation of blood flow were associated with favorable glucose homeostasis and ß-cell function. CONCLUSIONS: Bariatric surgery elicits marked alterations in pancreatic lipid metabolism and blood flow, which may contribute to the observed improvement in glucose homeostasis and remission of type 2 diabetes.

Pancreatic metabolism, blood flow, and ß-cell function in obese humans.

CONTEXT: Glucolipotoxicity is believed to induce pancreatic ß-cell dysfunction in obesity. Previously, it has not been possible to study pancreatic metabolism and blood flow in humans. OBJECTIVE: The objective of the study was to investigate whether pancreatic metabolism and blood flow are altered in obesity using positron emission tomography (PET). In the preclinical part, the method was validated in animals. DESIGN: This was a cross-sectional study. SETTING: The study was conducted in a clinical research center. PARTICIPANTS: Human studies consisted of 52 morbidly obese and 25 healthy age-matched control subjects. Validation experiments were done with rodents and pigs. INTERVENTIONS: PET and magnetic resonance imaging studies using a glucose analog ([(18)F]fluoro-2-deoxy-d-glucose), a palmitate analog [14(R,S)-[(18)F]fluoro-6-thia-heptadecanoic acid], and radiowater ([(15)O]H2O) were performed. In animals, a comparison between ex vivo and in vivo data was performed. MAIN OUTCOME MEASURES: Pancreatic glucose/fatty acid (FA) uptake, fat accumulation, and blood flow parameters of ß-cell function were measured. RESULTS: PET proved to be a feasible method to measure pancreatic metabolism. Compared with healthy participants, obese participants had elevated pancreatic FA uptake (P < .0001), more fat accumulation (P = .0001), lowered glucose uptake both during fasting and euglycemic hyperinsulinemia, and blunted blood flow (P < .01) in the pancreas. Blood flow, FA uptake, and fat accumulation were negatively associated with multiple markers of ß-cell function. CONCLUSIONS: Obesity leads to changes in pancreatic energy metabolism with a substrate shift from glucose to FAs. In morbidly obese humans, impaired pancreatic blood flow may contribute to ß-cell dysfunction and in the pathogenesis of type 2 diabetes.

The effect of revascularization of renal artery stenosis on renal perfusion in patients with atherosclerotic renovascular disease.

BACKGROUND: Only a small fraction of patients with atherosclerotic renovascular disease (ARVD) treated with revascularization have improved renal function after the procedure. It has been suggested that this may be due to effects of renal microvascular disease. Our aim was to measure the effect of renal artery stenosis (RAS) revascularization on renal perfusion in patients with renovascular disease. METHODS: Seventeen renovascular disease patients were treated by dilatation of unilateral (N = 8) or bilateral (N = 9) RAS (N = 23 kidneys), mainly because of uncontrolled or refractory hypertension. The patients were studied before and after (103 ± 29 days) the procedure. Renal perfusion was measured using quantitative positron emission tomography (PET) perfusion imaging. RESULTS: Although renal perfusion correlated inversely with the degree of RAS in patients with renovascular disease, it did not change after revascularization. CONCLUSIONS: Our data support the notion of former clinical trials that angiographic severity of RAS does not determine the response to revascularization. Quantitative PET perfusion imaging is a promising tool to noninvasively measure renal perfusion for the assessment of physiological impact of RAS.