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

Abstract

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.

Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine

“…FGF21 gene therapy is another way to overcome the unfavorable pharmacokinetic properties of native FGF21. Researchers administered an FGF21-overexpressing adeno-associated viral vector to mouse visceral adipose tissue, which decreases body weight and improves insulin sensitivity 130 . This study also highlights the potential of gene therapy to overexpress FGF21 in target tissues.…”

“…One study reported that injection with a liver-specific FGF21 expression nonviral plasmid in FGF21 knockout mice can restore FGF21 expression and regulate body mass 174 . Another study utilized an adeno-associated viral vector to express FGF21 in mouse visceral adipose tissue, which resulted in reduced whole-body adiposity and adipose tissue macrophage inflammation 130 . Moreover, researchers recently designed a novel FGF21 named LAPS-FGF21 with a longer half-life via conjugation to the Fc fragment of IgG4, which has shown an excellent therapeutic effect on obesity in mice 175 .…”

“…Table 1 shows the role of FGF21-based drugs in CVMDs. For metabolic disease, glucose and lipid profiles are fundamental factors in maintaining a healthy metabolism, which can be improved by FGF21 26 , 130 , 135 , 138 . Studies that investigated T2DM and FGF21 found that FGF21 can improve glucose homeostasis-related risk factors, such as glycated hemoglobin glycosylated hemoglobin A1c 142 , insulin 97 , and insulin resistance 108 .…”

Innate Immune System Orchestrates Metabolic Homeostasis and Dysfunction in Visceral Adipose Tissue During Obesity

“…Therefore, M2specific reduction of CD1d expression and alterations of APCs from M2 to M1 are important initiating events that switch iNKT cell-mediated immune responses from anti-inflammatory to proinflammatory activities and disrupt the immune balance in VAT of obese mice (23). AT-resident iNKT cells are also innate lipid sensors that play crucial roles in glycemic control and weight regulation in the steady state of VAT via the production of fibroblast growth factor 21 (FGF21) (24,25).…”

Efeitos do treinamento físico intervalado de alta intensidade (HIIT) nas características morfológicas e funcionais do tecido adiposo branco e marrom

“…Assim, aumentar a capacidade termogênica é apenas um dos efeitos que exerce63 . Para exemplificar, camundongos que expressam excessivamente FGF-21 no TAB-PE, mesmo na ausência de aumento na expressão da UCP1, apresentam redução da adiposidade total e da inflamação do TA, maior expressão de adiponectina e maior sensibilidade à insulina147 .Embora trabalhos na literatura tenham reportado o aumento da UCP1 no TAB-SC130,148,149 e no TAM149 de camundongos treinados com o HIIT, e no TAB-SC de camundongos treinados com o TFA74 , o conjunto de dados relacionados a capacidade termogênica dos três depósitos avaliados sugere que o HIIT não foi capaz de aumentá-la. O presente trabalho não é o primeiro a reportar a ausência de alterações na capacidade termogênica do TA com o HIIT.…”