Detection of brown adipose tissue and thermogenic activity in mice by hyperpolarized xenon MRI

The study of brown adipose tissue (BAT) in human weight regulation has been constrained by the lack of a noninvasive tool for measuring this tissue and its function in vivo. Existing imaging modalities are nonspecific and intrinsically insensitive to the less active, lipid-rich BAT of obese subjects, the target population for BAT studies. We demonstrate noninvasive imaging of BAT in mice by hyperpolarized xenon gas MRI. We detect a greater than 15-fold increase in xenon uptake by BAT during stimulation of BAT thermogenesis, which enables us to acquire background-free maps of the tissue in both lean and obese mouse phenotypes. We also demonstrate in vivo MR thermometry of BAT by hyperpolarized xenon gas. Finally, we use the linear temperature dependence of the chemical shift of xenon dissolved in adipose tissue to directly measure BAT temperature and to track thermogenic activity in vivo.Obesity is the result of an imbalance between energy intake and energy expenditure. The latter seems to be modulated, at least in part, by the activity of brown adipose tissue (BAT). BAT is a fatty tissue specialized in cold-induced and diet-induced thermogenesis, a metabolic activity during which this tissue burns fat to produce heat (1). Because of its high “fat-burning” capacity and its ability to regulate glucose homeostasis and insulin sensitivity (2, 3), this tissue is now considered to be the next target for antiobesity drugs (4). However, as interventions that aim to decrease body weight by increasing energy expenditure through BAT volume and/or activity modulations are being investigated (5, 6), the ability to detect this tissue in humans represents an unmet need. Current imaging techniques fail to detect BAT in the target population, obese and overweight subjects, and it is not clear whether this is due to a lack of BAT mass or BAT activity (7). For example, ¹⁸FluoroDeoxyGlucose Positron Emission Tomography (¹⁸FDG-PET), considered to be the gold standard for the detection of BAT activity, can detect BAT activity in morbidly obese and obese subjects only after bariatric surgery or substantial weight loss (8, 9). This is because ¹⁸FDG-PET can only be used to detect active BAT, and in obese subjects, activity is substantially reduced. In addition, the detection of BAT by ¹⁸FDG-PET is performed indirectly, through measurements of BAT uptake of glucose, which is not the primary fuel for BAT thermogenesis. Heat production in BAT is primarily fueled by oxidation of fatty acids released from triglycerides stored in the intracellular fat droplets (10), and, as such, measurements of exogenous glucose or exogenous fatty acid uptake are clearly intrinsically insensitive to BAT thermogenic activity (11, 12).In computed tomography (CT) and ¹H MRI studies, fat fraction measurements are used to differentiate the highly hydrated brown adipose tissue from the less hydrated normal white adipose tissue (WAT) (13–15). Unfortunately, human BAT is a heterogeneous mixture of white and brown adipocytes (16), and partial volume effects that arise from the limited spatial resolution of these imaging modalities make these types of measurements unreliable and nonspecific. Indeed, in one study in which ¹⁸FDG-PET BAT maps and MRI BAT maps were compared, areas that were BAT-positive for ¹⁸FDG-PET had the same fat fraction of nearby areas that were BAT-negative (17). Nonlinear MRI techniques based on intermolecular zero-quantum coherences between water and fat spins can be used to overcome partial volume effects and obtain background-free maps of BAT in lean phenotypes (18). However, in overweight and obese subjects, the strong reduction in tissue hydration and increase in the average distance between water and fat spins would cause a reduction of the already small nonlinear MR signal, making the entire detection unfeasible (18). More importantly, BAT hydration is not a good marker for BAT, as it is highly modulated by tissue thermogenic activity and therefore exhibits very high intersubject and intrasubject variability (19). For example, whereas in lean subjects BAT may have a fat fraction close to 50%, in obese subjects the BAT fat fraction is close to 80%, making it impossible to distinguish this tissue from the normal WAT with conventional fat fraction methods or more sophisticated nonlinear MR techniques.Other less expensive imaging modalities such as infrared thermography and contrast ultrasound have similar problems. BAT thermogenesis is still detected indirectly, either through surface temperature measurements (infrared thermography) that are inherently affected by local changes in tissue blood flow (20) or by measurements of tissue blood flow (ultrasound), which is only partially coupled to BAT thermogenic activity (11) and which exhibits the same insensitivity to the less vascularized lipid-rich BAT of obese phenotypes (21).Our primary goal with this study is to evaluate the possibility to detect BAT tissue and thermogenic activity by using hyperpolarized (HP) xenon gas MRI. In hyperpolarized xenon MRI studies, prior hyperpolarization of the gas through a process called spin-exchange optical pumping (SEOP) is the necessary step to make the gas MR-visible (22). After hyperpolarization, the gas can be inhaled by the subject or by the animal to visualize lung ventilation function (23), xenon gas exchange (23, 24), or other distal organs of interest (25). After inhalation the gas diffuses from the lung airspaces to the lung parenchyma and to the blood. The dissolved gas is then transported to distal organs, where it accumulates proportionally to tissue perfusion rate and to tissue–blood partition coefficient. More interestingly, as xenon diffuses in different tissue compartments, its chemical shift changes, making it possible to differentiate between xenon dissolved in blood and xenon dissolved in tissue or lipids. However, as the amount of xenon that is transferred at any given point in time from the lung airspaces to tissue–blood is relatively small, and as the T1 relaxation time of xenon in blood is relatively short, imaging of distal organs by hyperpolarized xenon gas remains a major challenge.Here we capitalize on the lipophilic nature of xenon and on the strong increase in blood flow to brown fat that occurs during stimulation of thermogenic activity to detect the highly vascularized BAT (26). In addition, we measure and use the chemical shift temperature coefficient of xenon dissolved in adipose tissue to directly detect its thermogenic activity in vivo.     

F-fluorodeoxyglucose uptake in brown adipose tissue during insulin-induced hypoglycemia and mild cold exposure in non-diabetic adults

Objective

Hypoglycemia is associated with increased heat production and, despite of this, hypothermia. Heat production is likely to be mediated by sympathetic innervation. Brown adipose tissue is activated by cold exposure and stimulated by the sympathetic nervous system. We therefore examined the effect of hypoglycemia on uptake of the labeled glucose analogue ¹⁸ F-fluorodeoxyglucose in brown adipose tissue using positron emission tomography and computer tomography.

Methods

In nine healthy adults ¹⁸ F-fluorodeoxyglucose uptake as measure of brown adipose tissue activity was assessed in a cold environment (17 °C) during euglycemia (blood glucose 4.5 mmol/L) and hypoglycemia (2.5 mmol/L) using a hyperinsulinemic glucose clamp.

Results

Brown adipose tissue activity was observed in all participants. No difference was observed in the median (range) maximal standardized uptake values of ¹⁸ F-fluorodeoxyglucose in brown adipose tissue between euglycemia and hypoglycemia: 4.2 (1.0–7.7) versus 3.1 (2.2–12.5) g/mL (p = 0.7). Similarly there were no differences in mean standardized ¹⁸ F-fluorodeoxyglucose uptake values or total brown adipose tissue volume between euglycemia and hypoglycemia. Body temperature dropped by 0.6 °C from baseline during the hypoglycemic condition and remained unchanged during the euglycemic condition. There was no correlation between the maximal standardized uptake values of ¹⁸ F-fluorodeoxyglucose in brown adipose tissue and levels of counterregulatory hormones.

Conclusions

This study shows that there is a similar amount of ¹⁸ F-fluorodeoxyglucose uptake in brown adipose tissue during hypoglycemia when compared to euglycemia, which makes a role for systemic catecholamines in brown adipose tissue activation and a role for brown adipose tissue thermogenesis in hypoglycemia associated hypothermia unlikely. Future studies in humans should determine whether hypoglycemia indeed increases energy expenditure, and if so which alternative source can explain this increase.     

Quantification of liver glucose metabolism by positron emission tomography: validation study in pigs

BACKGROUND & AIMS: The liver is inaccessible to organ balance measurements in humans. To validate [(18)F]fluorodeoxyglucose ([(18)F]FDG) positron emission tomography (PET) in the quantification of hepatic glucose uptake (HGU), we determined [(18)F]FDG modeling parameters, lumped constant (LC), and input functions (single arterial versus dual). METHODS: Anesthetized pigs were studied during fasting (n = 6), physiologic (n = 4), and supraphysiologic (n = 4) hyperinsulinemia. PET was performed with C(15)O (blood pool) and [(18)F]FDG (glucose uptake). 6,6-Deuterated glucose ([(2)H]G) was coinjected with [(18)F]FDG and blood collected from the carotid artery and portal and hepatic veins to compute LC as ratio between tracers fractional extraction. HGU was estimated from PET images and ex vivo from high-performance liquid chromatography measurements of liver [(18)F]FDG versus [(18)F]FDG-6-phosphate and [(18)F]-glycogen. Endogenous glucose production was measured with [(2)H]G and hepatic blood flow by flowmeters. RESULTS: HGU was increased in hyperinsulinemia versus fasting (P < .05). Fractional extraction of [(18)F]FDG and [(2)H]G was similar (not significant), intercorrelated (r = 0.98, P < .0001), and equally higher during hyperinsulinemia than fasting (P 0.95, P < .0001), with a modest underestimation of HGU by the former. CONCLUSIONS: [(18)F]FDG-PET-derived parameters provide accurate quantification of HGU and estimates of liver perfusion and glucose production. In the liver, LC of [(18)F]FDG is nearly unitary. Using a single arterial input introduces only a small error in estimation of HGU.     

Role of 18-fluoro-2-deoxyglucose positron emission tomography in detecting acute inflammatory lesions of non-bacterial osteitis in patients with a fever of unknown origin: A comparative study of 18-fluoro-2-deoxyglucose positron emission tomography,bone scan,and magnetic resonance imaging

Abstract

We report three patients with non-bacterial osteitis (NBO) who had fever of unknown origin (FUO) as an initial symptom. 18-Fluoro-2-deoxyglucose positron emission tomography (¹⁸F-FDG–PET) can be used to detect acute inflammatory lesions. There seems to be variation among the results of ¹⁸F-FDG–PET, a bone scan, and magnetic resonance imaging (MRI). Therefore, it would be useful to perform a bone scan to detect all lesions, combined with MRI to confirm the diagnosis of NBO, followed by ¹⁸F-FDG–PET.     

Thermogenic adipocytes: From cells to physiology and medicine

The identification of active brown fat in humans has evoked widespread interest in the biology of non-shivering thermogenesis among basic and clinical researchers. As a consequence we have experienced a plethora of contributions related to cellular and molecular processes in thermogenic adipocytes as well as their function in the organismal context and their relevance to human physiology. In this review we focus on the cellular basis of non-shivering thermogenesis, particularly in relation to human health and metabolic disease.     

Intravenous thrombolytic treatment of mechanical prosthetic valve thrombosis: a study using serial transesophageal echocardiography

OBJECTIVE

We analyzed the results of intravenous thrombolytic treatment under transesophageal echocardiographic (TEE) guidance in prosthetic valve thrombosis.

BACKGROUND

Thrombotic occlusion of prosthetic valves continues to be an uncommon but serious complication. Intravenous thrombolytic treatment has been proposed as an alternative to surgical intervention.

METHODS

In a four-year period, 32 symptomatic patients with prosthetic valve related thrombosis underwent 54 thrombolytic treatment sessions for the treatment of 36 distinct episodes. All patients had low international normalized ratio values at the presentation. Transesophageal echocardiography was performed at baseline and repeated after each thrombolytic treatment session (total 98 TEE examinations). Streptokinase was used as the initial agent with a repeat dose given within 24 h when necessary. Recurrent thrombosis was treated either with tissue plasminogen activator or urokinase.

RESULTS

The initial success after first dose was only 53% (17/32) but increased up to 88% (28/32) after repeated thrombolytic sessions upon documentation of suboptimal results on TEE examination (p < 0.01). In addition, four asymptomatic patients with large thrombi were also successfully treated with single infusion. The TEE characteristics of thrombus correlated with clinical presentation and response to lytics. Success was achieved with single lytic infusion in 40% of the obstructive thrombi as compared with 75% of the nonobstructive ones (p < 0.05). The success rates of lytic treatment were similar for mitral versus aortic valves, and for tilting disk versus bileaflet valves. Rapid (3 h) and slow (15 to 24 h) infusion of streptokinase resulted in similar success rates. However, major complications (three patients) occurred only in the rapid infusion group.

CONCLUSION

In patients with prosthetic valve thrombosis, intravenous slow infusion thrombolysis given in discrete, successive sessions guided by serial TEE and transthoracic echocardiography can be achieved with a low risk of complications and a high rate of success.     

Epicardial adipose tissue volume as a marker of coronary artery disease severity in patients with diabetes independent of coronary artery calcium: Findings from the CTRAD study

AimsThe association between epicardial adipose tissue (EAT) volume and coronary artery disease (CAD) severity was evaluated, independent of traditional risk factors and coronary artery calcium (CAC) scores, in patients with diabetes type 2 (DM-2) using cardiac computed tomography angiography (CTA).MethodsA multivariate analysis was utilized to assess for an independent association after calculating EAT volume, CAD severity, and calcium scores in 92 patients with DM-II from the CTRAD study. We graded CAD severity as none (normal coronaries), mild-moderate (<70% stenosis), and severe (70% or greater stenosis).ResultsA total of 39 (42.3%) asymptomatic patients with diabetes did not have CAD; 30.4% had mild/moderate CAD; and 27.1% had severe CAD. Mean EAT volume was highest in patients with severe CAD (143.14 cm³) as compared to mild/moderate CAD (112.7 cm³), and no CAD (107.5 cm³) (p = 0.003). After adjustment of clinical risk factors, notably, CAC score, multivariate regression analysis showed EAT volume was an independent predictor of CAD severity in this sample (odds ratio 11.2, 95% confidence interval 1.7–73.8, p = 0.01).ConclusionsIncreasing EAT volume in asymptomatic patients with DM-II is associated with presence of severe CAD, independent of BMI and CAC, as well as traditional risk factors.