Decreased Sympathetic Innervation of Cold-activated Brown and White Fat in Obese Subjects using 11C-HED PET Imaging

Introduction: As obesity is the result of a mismatch between energy intake and energy expenditure, one possible strategy for weight management in obesity is to increase energy consumption. Within this context, the activation of both brown and white adipose tissue (BAT and WAT) has been suggested as a promising means of increasing energy expenditure through the activation of non-shivering thermogenesis. However, the relevance of both BAT and WAT activation for weight management in obesity is unclear, as there is clear evidence for an inverse relationship between BAT mass and BMI. The objective of the present study was to investigate the relationship between sympathetic innervation and energy expenditure in both BAT and subcutaneous/visceral WAT in a group of obese and lean subjects during cold exposure.

Methods: Two groups were studied: a group of obese adult subjects (5F/5M, age 31.4 <u>+</u> 7.2 years, BMI = 34.1 <u>+</u> 3.2) and a group of lean controls (5F/5M, age 26.1 <u>+</u> 6.1 years, BMI = 22.8 <u>+</u> 2.2). All subjects underwent 11C-meta-hydroxyephedrin (11C-HED) and 15O-water PET imaging using a GE DSTE PET/CT scanner at rest and after exposure to mild cold (16^oC). In addition, 18F-FDG images were obtained during the cold stress condition to assess the presence of activated BAT. Mild cold exposure was applied using a specialized whole-body garment (Figure 1). In addition, measurement of daily energy expenditure (DEE, kcal/d) under resting and cold conditions was performed using the VO2000 Portable Metabolic Testing System. Regional time–activity curves were derived from 15O-water and 11C-HED scans during both thermoneutral and cold conditions and blood flow F (mL/ g/min) and 11C-HED Retention Index (RI, an index of sympathetic innervation) were estimated as described previously (Muzik et al., JNM 2017,58:799). F and RI during thermoneutral and cold conditions were determined for supraclavicular BAT, subcutaneous and visceral WAT as well as for one deep, centrally located muscle (psoas).

Results: All subjects in the lean group had a BMI within the normal range (19-25 kg/m², mean = 22.8 <u>+</u> 2.2) which was significantly lower than the BMI in the obese group (BMI > 30 kg/m², mean = 34.1 <u>+</u> 3.2, p < 0.001). Resting DEE was found to be significantly higher in the obese as compared to the lean group (2039 <u>+</u> 466 vs 1465 <u>+</u> 408 kcal/d, p = 0.02), however, the DEE during cold exposure was not significantly different between the groups due to an average decrease (~ 3%) of DEE observed in the obese group during cold exposure (1991 <u>+</u> 361kcal/d) but an ~20% increase in DEE in the lean group (1728 <u>+</u> 436 kcal/d). Specifically, whereas in the lean group the DEE was always increased during cold, DEE was decreased in 6/8 obese subjects. Sympathetic innervation in BAT was significantly lower in the obese group at both rest and cold conditions as compared to the lean group (RI = 0.58 <u>+</u> 0.15 vs 2.42 <u>+</u> 1.39 at rest and 1.23 <u>+</u> 0.31 vs 3.34 <u>+</u> 1.69 at cold, Figure 2) which was also reflected in BAT blood flow (F = 3.2 <u>+</u> 0.5 vs 8.4 <u>+</u> 4.3 ml/100g/min at rest vs 7.3 <u>+</u> 4.5 vs 12.5 <u>+</u> 3.7 ml/100g/min at cold). In addition, RI decreased during cold exposure in both subcutaneous (from 0.32 + 0.16 to 0.27 <u>+</u> 0.12, %diff = -10%) as well as visceral WAT (from 0.59 <u>+</u> 0.23 to 0.48 <u>+</u> 0.13, %diff = -13%), a decrease twice as large as observed in lean subjects (about -5%). Finally, sympathetic innervation in obese subjects was increased during cold in the psoas (RI = 0.93 <u>+</u> 0.26 to 1.30 <u>+</u> 0.43), similar to values determined in lean subjects (RI = 0.87 <u>+</u> 0.24 to 1.44 <u>+</u> 0.33), suggesting an active role of deep muscle in heat generation during cold.

Conclusions: Our results indicate that the contribution of WAT to DEE in obese subjects is negative as a result of decreased sympathetic innervation and blood flow. This decrease is more pronounced in obese as compared to lean subjects. These findings confirms that the primary function of WAT in obese subjects is insulatory and not heat generating.

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