Assessment of Oxidative Metabolism in Brown Fat Using PET Imaging

Abstract

Objective: Although it has been believed that brown adipose tissue (BAT) depots disappear shortly after the perinatal period in humans, positron emission tomography (PET) imaging using the glucose analog 18F-deoxy-d-glucose (FDG) has shown unequivocally the existence of functional BAT in humans, suggesting that most humans have some functional BAT. The objective of this study was to determine, using dynamic oxygen-15 (15O) PET imaging, to what extent BAT thermogenesis is activated in adults during cold stress and to establish the relationship between BAT oxidative metabolism and FDG tracer uptake. Methods: Fourteen adult normal subjects (9F/5M, 30 ± 7 years) underwent triple oxygen scans (H215O, C15O, 15O2) as well as indirect calorimetric measurements at both rest and following exposure to mild cold (16°C). Subjects were divided into two groups (BAT+ and BAT−) based on the presence or absence of FDG tracer uptake (SUV > 2) in cervical–supraclavicular BAT. Blood flow and oxygen extraction fraction (OEF) was calculated from dynamic PET scans at the location of BAT, muscle, and white adipose tissue (WAT). The metabolic rate of oxygen (MRO2) in BAT was determined and used to calculate the contribution of activated BAT to daily energy expenditure (DEE). Results: The median mass of activated BAT in the BAT+ group (5F, age 31 ± 8) was 52.4 g (range 14–68 g) and was 1.7 g (range 0–6.3 g) in the BAT − group (5M/4F, age 29 ± 6). Corresponding SUV values were significantly higher in the BAT+ as compared to the BAT− group (7.4 ± 3.7 vs. 1.9 ± 0.9; p = 0.03). Blood flow values in BAT were significantly higher in the BAT+ group as compared to the BAT− group (13.1 ± 4.4 vs. 5.7 ± 1.1 ml/100 g/min, p = 0.03), but were similar in WAT (4.1 ± 1.6 vs. 4.2 ± 1.8 ml/100 g/min) and muscle (3.7 ± 0.8 vs. 3.3 ± 1.2 ml/100 g/min). Moreover, OEF in BAT was similar in the two groups (0.56 ± 0.18 in BAT+ vs. 0.46 ± 0.19 in BAT−, p = 0.39). Calculated MRO2 values in BAT increased from 0.95 ± 0.74 to 1.62 ± 0.82 ml/100 g/min in the BAT+ group and were significantly higher than those determined in the BAT− group (0.43 ± 0.27 vs. 0.56 ± 0.24, p = 0.67). The DEE associated with BAT oxidative metabolism was highly variable in the BAT+ group, with an average of 5.5 ± 6.4 kcal/day (range 0.57–15.3 kcal/day). Conclusion: BAT thermogenesis in humans accounts for less than 20 kcal/day during moderate cold stress, even in subjects with relatively large BAT depots. Furthermore, due to the large differences in blood flow and glucose metabolic rates in BAT between humans and rodents, the application of rodent data to humans is problematic and needs careful evaluation.

Brown Adipose Tissue in Humans

“…HERE --Cold activation enhances hBAT perfusion significantly when studied using 15 O--H2O--PET (Orava et al 2011, Muzik et al 2012. Insulin stimulation during euglycemia increases BAT glucose uptake five--fold in line with whole body insulin sensitivity but without any increment in perfusion (Orava et al 2011).…”

“…Insulin stimulation during euglycemia increases BAT glucose uptake five--fold in line with whole body insulin sensitivity but without any increment in perfusion (Orava et al 2011). When Muzik and co--workers used 15 O2 to assess directly oxygen consumption during cold stimulation, MRO2 values were shown to increase (Muzik et al 2012). Based on this, the authors estimated that thermogenesis of supraclavicular BAT depots account less than 20 kcal/day.…”

“…PET is a highly sensitive and specific imaging tool for studies of BAT physiology (Table 1). (Orava et al 2011, Muzik et al 2012 [ (Virtanen et al 2009, Orava et al 2011 Free fatty acid metabolism (Ouellet et al 2012) [ 18 F]FTHA 109…”

“…Relative to FDG, this numerical value has been shown to approximate unity in skeletal muscle (Peltoniemi et al 2000), myocardium (Ng et al 1998) and adipose tissue (Virtanen et al 2001), and to hold constant across metabolic disease states. Therefore it has been assumed to be 1.0 also for human BAT (Virtanen 2009 (Iida et al, 1988, Ruotsalainen et 1997 and applied to the study of BAT as well (Orava et al 2011, Muzik et al 2012. Oxygen consumption may be determined directly in BAT using 15 O2--PET (Muzik et al 2012).…”

“…Therefore it has been assumed to be 1.0 also for human BAT (Virtanen 2009 (Iida et al, 1988, Ruotsalainen et 1997 and applied to the study of BAT as well (Orava et al 2011, Muzik et al 2012. Oxygen consumption may be determined directly in BAT using 15 O2--PET (Muzik et al 2012). This tracer is given by inhalation and requires on--site blood radioactivity measurement or the use of image--derived input function for the modeling.…”