Visceral adipose tissue-directed FGF21 gene therapy improves metabolic and immune health in BTBR mice

• Published in: Molecular therapy. Methods & clinical development 2021-03, Vol.20, p.409-422
• Main Authors: Queen, Nicholas J., Bates, Rhiannon, Huang, Wei, Xiao, Run, Appana, Bhavya, Cao, Lei
• Format: Article
• Language: English
• Subjects: AAV; adeno-associated virus; adipose; adipose tissue macrophages; fat; FGF21; gene therapy; obesity; Original; type 2 diabetes; visceral
• ISSN: 2329-0501; 2329-0501
• DOI: 10.1016/j.omtm.2020.12.011

Fibroblast growth factor 21 (FGF21) is a peptide hormone that serves as a potent effector of energy homeostasis. Increasingly, FGF21 is viewed as a promising therapeutic agent for type 2 diabetes, fatty liver disease, and other metabolic complications. Exogenous administration of native FGF21 peptide has proved difficult due to unfavorable pharmacokinetic properties. Here, we utilized an engineered serotype adeno-associated viral (AAV) vector coupled with a dual-cassette design to selectively overexpress FGF21 in visceral adipose tissue of insulin-resistant BTBR T+Itpr3tf/J (BTBR) mice. Under high-fat diet conditions, a single, low-dose intraperitoneal injection of AAV-FGF21 resulted in sustained benefits, including improved insulin sensitivity, glycemic processing, and systemic metabolic function and reduced whole-body adiposity, hepatic steatosis, inflammatory cytokines, and adipose tissue macrophage inflammation. Our study highlights the potential of adipose tissue as a FGF21 gene-therapy target and the promise of minimally invasive AAV vectors as therapeutic agents for metabolic diseases. [Display omitted] Queen et al. utilize an engineered viral vector to administer FGF21 gene therapy within adipose tissue in a non-invasive manner. As a result, metabolic health was improved and obesity-associated adipose immune signatures were reduced in a mouse model of dysregulated metabolism.