Xenon-enhanced computed tomography assessment of brown adipose tissue distribution and perfusion in lean, obese, and diabetic primates

Abstract

Objective: This study aimed to validate xenon-enhanced computed tomography (XECT) for the detection of brown adipose tissue (BAT) and to use XECT to assess differences in BAT distribution and perfusion between lean, obese, and diabetic nonhuman primates (NHPs).

Methods: Whole-body XECT imaging was performed in anesthetized rhesus and vervet monkeys during adrenergic stimulation of BAT thermogenesis. In XECT images, BAT was identified as fat tissue that, during xenon inhalation, underwent significant radiodensity enhancement compared with subcutaneous fat. To measure BAT blood flow, BAT radiodensity enhancement was measured over time on the six computed tomography scans acquired during xenon inhalation. Postmortem immunohistochemical staining was used to confirm imaging findings.

Results: XECT was able to correctly identify all BAT depots that were confirmed at necropsy, enabling construction of the first comprehensive anatomical map of BAT in NHPs. A significant decrease in BAT perfusion was found in diabetic animals compared with obese animals and healthy animals, as well as absence of axillary BAT and significant reduction of supraclavicular BAT in diabetic animals compared with obese and lean animals.

Conclusions: The use of XECT in NHP models of obesity and diabetes allows the analysis of the impact of metabolic status on BAT mass and perfusion.

FIGURE 1

Radiodensity enhancement observed in computed tomography images during xenon inhalation and norepinephrine infusion in the (A) supraclavicular, (B,D) axillary, and (C) renal hilum regions of a lean healthy rhesus macaque [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 2

Widespread supraclavicular BAT observed on XECT (Figure 1) visualized during (A) necropsy and (B) confirmed by histology with UCP1 staining. Large axillary BAT pockets seen on XECT in the same rhesus macaque were confirmed at (C) necropsy and (D) by UCP1 staining. BAT, brown adipose tissue; UCP1, uncoupling protein 1; XECT, xenon‐enhanced computed tomography [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 3

(A) Large areas of radiodensity enhancement observed on CT images during norepinephrine infusion and xenon inhalation in the supraclavicular region of a prediabetic rhesus macaque. (B,D) Limited axillary radiodensity enhancement was seen on XECT of the same rhesus macaque, and (C) no enhancement in the renal hilum was observed. CT, computed tomography; XECT, xenon‐enhanced computed tomography [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 4

Pockets of supraclavicular BAT seen on XECT of a prediabetic rhesus macaque (Figure 3) were visualized during (A) necropsy and confirmed on (B) histology with UCP1 staining. Limited axillary radiodensity enhancement on XECT of the same rhesus macaque (Figure 3) was consistent with little BAT observation during (C) necropsy and histology with (D) UCP1 staining. BAT, brown adipose tissue; UCP1, uncoupling protein 1; XECT, xenon‐enhanced computed tomography [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 5

Representative differences in radiodensity enhancement observed in the supraclavicular region during norepinephrine infusion and xenon inhalation between (A) healthy lean vervet monkey (NHP 1080), (B) healthy obese vervet monkey (NHP 1299), and (C) diabetic vervet monkey (NHP 1242). Images on the left were acquired before xenon inhalation. Images on the right were acquired during xenon inhalation. Representative images showing the difference in radiodensity enhancement observed in the axillary region of (D) healthy lean vervet monkey (NHP 1080), (E) healthy obese vervet monkey (NHP 1299), and (F) diabetic vervet monkey (NHP 1242) before (left) and during (right) xenon inhalation. Intensity scale for all figures ranges from −150HU to +150 HU. NHP, nonhuman primate [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 6

Three‐dimensional segmentation of brown adipose tissue depots identified using xenon‐enhanced computed tomography in (A) healthy lean vervet monkey (NHP 1080), (B) healthy obese vervet monkey (NHP 1299), and (C) diabetic vervet monkey (NHP 1242). NHP, nonhuman primate [Color figure can be viewed at wileyonlinelibrary.com]

FIGURE 7

(A) Mean BAT perfusion calculated in selected regions of interest in the supraclavicular and axillary regions of HL (n = 3), HO (n = 3), Pre‐D (n = 1), and D (n = 4) vervet monkeys. Three ROIs were taken from each of the two anatomical regions of each animal for a total of n = 6 ROIs from each vervet monkey. Error bars represent SD. (B) Mean BAT perfusion in selected regions of interest of the supraclavicular and axillary regions of each vervet monkey (n = 11). Connected points correspond to the same subject. A matched‐pairs t test revealed significantly greater perfusion in supraclavicular BAT compared with axillary BAT (mean difference ± SE of 0.20 ± 0.06 s⁻¹, p = 0.0009). (C) BAT perfusion calculated in selected ROIs in the supraclavicular (blue) and axillary (orange) regions of HL (n = 3), HO (n = 3), Pre‐D (n = 1), and D (n = 4) vervet monkeys. A Tukey–Kramer honestly significant difference test for multiple comparisons demonstrated significantly greater flow in HL primates than in HO (p = 0.0160) and unhealthy (Pre‐D and D) primates (p < 0.0001). Additionally, significantly greater blood flow was detected in HO primates than unhealthy primates (p = 0.0008). BAT, brown adipose tissue; D, diabetic; HL, healthy lean; HO, healthy obese; Pre‐D, prediabetic; ROI, region of interest [Color figure can be viewed at wileyonlinelibrary.com]