ORF50-04 - Tirzepatide Stimulates Brown Adipose Tissue Activity Independent of Weight Loss in Women with Obesity: TABFAT Trial

Background: Brown adipose tissue (BAT) is a compelling therapeutic target against metabolic diseases with a potential to impact energy expenditure. Tirzepatide has demonstrated robust weight loss effect, primarily through reduced energy intake. However, the effects of tirzepatide on activation of BAT remain unknown.

Design: We conducted a 24-week, single-blinded, randomized, placebo-controlled trial in 34 women with obesity (median age 39.5 [35.5–45.0] years; BMI 36.9 [34.5–39.2] kg/m²), randomized in a 1:1 ratio to once-weekly subcutaneous tirzepatide (mean dose 8.8 ± 1.3 mg) or placebo (NCT04263415).

Methods: BAT was assessed before and after the intervention using cold-stimulated [18F]FDG-PET/CT with personalized cooling protocols, where the temperature was adjusted to each participant’s predetermined shivering threshold. In addition, BAT was assessed by thermoneutral MRI. Resting energy expenditure (REE) was measured by indirect calorimetry. In a subset of tirzepatide-treated participants with BAT activation, exploratory quantitative PCR (qPCR) analysis of thermogenic and mitochondrial genes in adipose tissue biopsies was performed.

Results: Tirzepatide increased [¹⁸F]FDG-PET/CT-detectable BAT activity in a significant proportion of subjects (41.2% at baseline vs. 64.7% after intervention), while no change in detection was noticed in the placebo group (p = 0.005). In the tirzepatide group, cold-stimulated BAT metabolic activity and volume increased significantly, including SUVmean (p = 0.014), SUVpeak (p = 0.026), total metabolically active BAT volume (TMBATV; p = 0.021), and total BAT activity (TMBATA; p = 0.016). Absolute changes in SUVmean, TMBATV, and TMBATA were significantly greater compared with placebo (all p < 0.05). MRI-based assessment of supraclavicular BAT fat fraction reduction demonstrated changes consistent with [¹⁸F]FDG-PET/CT–measured BAT activation in the tirzepatide group (p < 0.001). Median weight loss with tirzepatide was 13.5% (−19.3 to −8.3%). Changes in body weight were not associated with changes in any PET/CT BAT parameters (all p > 0.4). REE did not differ significantly between groups; however, a numerically greater REE decline was observed in tirzepatide-treated participants without BAT activation (p = 0.3). Exploratory qPCR analysis in a subset of tirzepatide-treated participants with BAT activation showed increased expression of selected thermogenic and mitochondrial genes.

Conclusions: Tirzepatide stimulates BAT activity independent of weight loss in women with obesity. These results suggest a potential new mechanism for BAT activation.