Aims Cold stress has been shown to produce dramatic increases in 2-fluoro-2-deoxy-D-Glucose (18FDG) accumulation by brown adipose tissue (BAT) in rodents. However, neither the effects of other types of stress on 18FDG accumulation nor the effects of stressors on the accumulation of tracers of other aspects of energy metabolism have been evaluated. In this report we studied the effects of cold stress, burn injury, and cutaneous wounds on murine BAT at the macroscopic, microscopic, and metabolic level. Main Methods Glucose metabolism was studied with 18FDG, fatty acid accumulation was evaluated with trans-9(RS)-18F-fluoro-3,4(RS,RS)- methyleneheptadecanoic acid (FCPHA) and tricarboxcylic acid cycle (TCA) activity was evaluated with 3H acetate. Key Findings All three stressors produced dramatic changes in BAT at the macroscopic and microscopic level. Macroscopically, BAT from the stressed animals appeared to be a much darker brown in color. Microscopically BAT of stressed animals demonstrated significantly fewer lipid droplets and an overall decrease in lipid content. Accumulation of 18FDG by BAT was significantly (P <0.01) increased by all 3 treatments (Cold: ∼16 fold, burn ∼7 Fold and cutaneous wound ∼14 fold) whereas uptake of FDG by white fat was unchanged. This effect was also demonstrated non- invasively by μPET imaging. Although less prominent than with 18FDG, BAT uptake of FCPHA and acetate were also significantly increased by all three treatments. These findings suggest that in addition to cold stress, burn injury and cutaneous wounds produce BAT activation in mice. Significance This study demonstrates brown fat activated by several stressors leads to increased uptake of various substrates.

Infection is the most common and most serious complication of a major burn injury related to burn size. Despite improvements in antimicrobial therapies sepsis still accounts for 50–60% of deaths in burn patients. Given the acute onset and unpredictable nature of sepsis, primary prevention was rarely attempted in its management. However, recent studies have demonstrated that statin treatment can decrease mortality is a murine model of sepsis by preservation of cardiac function and reversal of inflammatory alterations. In addition, it has been shown that treatment with statins is associated with reduced incidence of sepsis in human patients. In the current study groups of CD1 male mice (n=12) were anesthetized and subjected to a dorsal 30% TBSA scald burn injury. Starting 2 hours post burn, the animals were divided into a treatment group receiving 0.2 µ/g simvastatin or a sham group receiving placebo. Simvastatin and placebo were administered by intraperitoneal injection with two dosing regimens; once daily and every 12 hours. On Post burn day 7 cecal ligation and puncture with a 21-gauge needle was performed under ketamine/xylazine anesthesia and the two different dosing schedules were continued. A simvastatin dose dependant improvement in survival was observed in the burn sepsis model.

Previous studies have demonstrated that cold stress results in increased accumulation of 18FDG in brown adipose tissue (BAT). Although it has been assumed that this effect is associated with increased thermogenesis by BAT, direct measurements of this phenomenon have not been reported. In the current investigation we evaluated the relationship between stimulation of 18FDG accumulation in BAT by three stressors and heat production measured in vivo by thermal imaging. Male SKH-1 hairless mice were subjected to full-thickness thermal injury (30% total body surface area), cold stress (4°C for 24 hours), or cutaneous wounds. Groups of 6 animals with each treatment were fasted over night and injected with 18FDG. Sixty minutes after injection the mice were sacrificed and biodistribution was measured. Other groups of six animals subjected to the three stressors were studied by thermal imaging and the difference in temperature between BAT and adjacent tissue was recorded (ΔT). Additional groups of 6 animals were studied by both thermal imaging and 18FDG biodistribution in the same animals. Accumulation of 18FDG by BAT was significantly (p <0.0001) increased by all 3 treatments (burn ~5 fold, cold: ~15 fold, and cutaneous wound ~15 fold) whereas accumulation by adjacent white adipose tissue (WAT) was unchanged. Compared with sham control mice; ΔTs in animals exposed to all three stressors showed significant (p<0.001) increases in temperature between BAT and adjacent tissue. The difference in ΔT between stressor groups was not significant, however, there was a highly significant linear correlation (r2=0.835, p<0.0001) between the ΔT measured in BAT vs. adjacent tissue and 18FDG accumulation. These results establish, for the first time, that changes in BAT temperature determined in vivo by thermal imaging parallel increases in 18FDG accumulation.