Introduction and Objective: Induced adipocyte browning, in limited subcutaneous adipose tissue (SAT) human depots via cold activation or weight loss, confers anti-diabetic/obesity function via thermogenesis. Peroxisome proliferator-activated receptor-γ coactivator (PGC1-α) regulates mitochondrial biogenesis in adipose tissue (AT), and may activate telomerase reverse transcriptase (TERT), which regulates cellular aging. AT browning exists in GLP-1RA-treated patients with weight loss, though it remains unclear if browning is a cause or consequence of GLP-1RA therapy. We investigate short-term dulaglutide therapy (GLP-1RA), prior to weight loss, on human SAT.Methods: Fifteen human subjects (11 F /4 M, 38±1 years, BMI 31.6±0.7 mg/kg2, HbA1C 5.5±0.01%) participated in a single center, crossover, placebo-controlled prospective trial. Subjects received dulaglutide (1.5 mg sc weekly) or vitamin B12 placebo for 6 weeks, then 3-week washout period, then opposite drug/placebo for 6 weeks. After each 6-week period, subjects underwent temperature stabilization followed by blood draw and PET-CT, followed by CT-guided biopsy of supraclavicular SAT. SAT was analyzed via qRT-PCR, and plasma was assessed for insulin metabolism. Based on remaining SAT cDNA, additional analyses were then conducted on a subset (n=11) to further investigate PGC1-α metabolism.Results: Weight did not change after 6 weeks of B12 or dulaglutide. Plasma GLP-1 was higher in dulaglutide (p<0.0001), with no group differences for HOMA-IR, insulin, free fatty acids, or glucose. SUV measurements for PET-CT showed no differences. However, SAT Pgc1-α mRNA increased with dulaglutide (p=0.07) with no notable differences in UCP1, PRDM16, and IL6 mRNA. In the subset, SAT Pgc1-α mRNA increased with dulaglutide (p=0.05), along with trend toward TERT increase (p=0.26).Conclusion: Pgc1-α might play a weight-independent role in human GLP-1-induced SAT browning and TERT activation. Larger human studies might unveil Pgc1-α-related pathways as new therapeutic targets.
A.D. Gutierrez: None. Z. Gao: None. H. Wang: None. M. Lee: None. S. Wilbon: None. M. Kolonin: None.
NIH NIDDK (5R21DK122234)
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