Variable Cold-Induced Brown Adipose Tissue Response to Thyroid Hormone Status.

BACKGROUND: In addition to its role in adaptive thermogenesis, brown adipose tissue (BAT) may protect from weight gain, insulin resistance/diabetes, and metabolic syndrome. Prior studies have shown contradictory results regarding the influence of thyroid hormone (TH) levels on BAT volume and activity. The aim of this pilot study was to gain further insights regarding the effect of TH treatment on BAT function in adult humans by evaluating the BAT mass and activity prospectively in six patients, first in the hypothyroid and then in the thyrotoxic phase. METHODS: The study subjects underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scanning after cold exposure to measure BAT mass and activity while undergoing treatment for differentiated thyroid cancer, first while hypothyroid following TH withdrawal at the time of the radioactive iodine treatment and then three to six months after starting TH suppressive treatment when they were iatrogenically thyrotoxic. Thermogenic and metabolic parameters were measured in both phases. RESULTS: All study subjects had detectable BAT under cold stimulation in both the hypothyroid and thyrotoxic state. The majority but not all (4/6) subjects showed an increase in detectable BAT volume and activity under cold stimulation between the hypothyroid and thyrotoxic phase (total BAT volume: 72.0 ± 21.0 vs. 87.7 ± 16.5 mL, p = 0.25; total BAT activity 158.1 ± 72.8 vs. 189.0 ± 55.5 SUV*g/mL, p = 0.34). Importantly, circulating triiodothyronine was a stronger predictor of energy expenditure changes compared with cold-induced BAT activity. CONCLUSIONS: Iatrogenic hypothyroidism lasting two to four weeks does not prevent cold-induced BAT activation, while the use of TH to induce thyrotoxicosis does not consistently increase cold-induced BAT activity. It remains to be determined which physiological factors besides TH play a role in regulating BAT function.

Quantification of human and rodent brown adipose tissue function using 99mTc-methoxyisobutylisonitrile SPECT/CT and 18F-FDG PET/CT.

UNLABELLED: For brown adipose tissue (BAT) to be effective at consuming calories, its blood flow must increase enough to provide sufficient fuel to sustain energy expenditure and also transfer the heat created to avoid thermal injury. Here we used a combination of human and rodent models to assess changes in BAT blood flow and glucose utilization. METHODS: (99m)Tc-methoxyisobutylisonitrile (MIBI) SPECT (n = 7) and SPECT/CT (n = 74) scans done in adult humans for parathyroid imaging were reviewed for uptake in regions consistent with human BAT. Site-directed biopsies of subcutaneous and deep neck fat were obtained for electron microscopy and gene expression profiling. In mice, tissue perfusion was measured with (99m)Tc-MIBI (n = 16) and glucose uptake with (18)F-FDG (n = 16). Animals were kept fasting overnight, anesthetized with pentobarbital, and given intraperitoneally either the ß3-adrenergic receptor agonist CL-316,243, 1 mg/kg (n = 8), or saline (n = 8) followed by radiotracer injection 5 min later. After 120 min, the mice were imaged using SPECT/CT or PET/CT. Vital signs were recorded over 30 min during the imaging. BAT, white adipose tissue (WAT), muscle, liver, and heart were resected, and tissue uptake of both (99m)Tc-MIBI and (18)F-FDG was quantified by percentage injected dose per gram of tissue and normalized to total body weight. RESULTS: In 5.4% of patients (4/74), (99m)Tc-MIBI SPECT/CT showed increased retention in cervical and supraclavicular fat that displayed multilocular lipid droplets, dense capillary investment, and a high concentration of ovoid mitochondria. Expression levels of the tissue-specific uncoupling protein-1 were 180 times higher in BAT than in subcutaneous WAT (P < 0.001). In mice, BAT tissue perfusion increased by 61% (P < 0.01), with no significant changes in blood flow to WAT, muscle, heart, or liver. CL-316,243 increased glucose uptake in BAT even more, by 440% (P < 0.01). CONCLUSION: Pharmacologic activation of BAT requires increased blood flow to deliver glucose and oxygen for thermogenesis. However, the glucose consumption far exceeds the vascular response. These findings demonstrate that activated BAT increases glucose uptake beyond what might occur by increased blood flow alone and suggest that activated BAT likely uses glucose for nonthermogenic purposes.