Glucagon-like Peptide-1 Receptor Agonists Promote Sympathetic Innervation in Mouse Adipose Tissues

Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used to treat obesity. However, their mechanism of action on adipose tissues remains incompletely understood. Methods: We exploited advanced three-dimensional imaging to investigate the effects of GLP-1RAs on sympathetic innervation in mouse adipose tissues. Results: Semaglutide or tirzepatide robustly promotes sympathetic innervation in inguinal white adipose tissue (iWAT) and interscapular brown adipose tissue (iBAT) but not in the liver tissues of mice with high-fat diet (HFD)-induced obesity. In addition, the sympathetic-promoting effect of tirzepatide occurs in the iWAT and iBAT of aged mice. Conversely, pharmacological ablation of sympathetic inputs results in alterations in adipocyte morphology and metabolic markers in GLP-1RA-treated HFD-fed mice. Moreover, GLP-1R is detected in neurons in the paraventricular nucleus of the hypothalamus of mice, a key brain region that elicits peripheral sympathetic signals, and semaglutide can effectively activate those neurons. Conclusions: These results provide new insights into the potential involvement of sympathetic action in adipose response to GLP-1RA treatment.