OR01-3 MicroRNA-34a-Mediated FGF21 Resistance in the Adipose Tissue Contributes to Insulin Resistance and Hypoadiponectinemia in Diet-Induced Obesity

Background and Objective: Fibroblast growth factor 21 (FGF21) is a metabolic hormone with multiple beneficial effects on glucose and lipid homeostasis, in part mediated through its stimulatory effect on adiponectin secretion. However, FGF21 circulating levels are paradoxically elevated in obesity, type 2 diabetes and other obesity-related disorders, suggesting the presence of FGF21 resistance in obesity. MicroRNA-34a (miR-34a) is the most highly elevated microRNA in white adipose tissues of obese mice and a conserved miR-34a seed sequence had been detected within the 3’UTR of FGFR1 and β-klotho. Here we sought to investigate the mediatory role of miR-34a in FGF21resistance. Methods: miR-34a expression and the corresponding changes in the expression of FGFR1 and β-klotho were assessed in visceral adipose tissue from mice with or without diet-induced obesity (DIO). Luciferase assay was used to examine the binding capacity of miR-34a to the FGF21 receptor complex. The ability to reverse FGF21 resistance via inhibiting adipose miR-34a in vivo was evaluated by both lentivirus-mediated miR-34a sponge and adipose tissue specific genetic depletion. Results: A consistent elevation of miR-34a expression in the adipose tissue was observed during the development of DIO, accompanied by a progressive increase in serum FGF21 levels. Following a transient increase at 4 weeks, mRNA levels of FGFR1 and β-klotho markedly decreased with DIO, accompanied by progressive resistance to the actions of exogenous FGF21, in terms of lowering of hyperglycemia and hyperinsulinemia, and adiponectin stimulation. Site-directed mutagenesis and luciferase activity studies showed that miR-34a suppressed the expression of FGFR1 and β-klotho and also adiponectin secretion. Blocking miR-34a actions by in vivo lentivirus-mediated miR-34a sponge or adipose tissue specific gene knock-out counteracted the reduction of FGFR1 and β-klotho expressions in mice with DIO and restored the ability of FGF21 to induce adiponectin secretion in their adipose tissue. Conclusion: During the development of obesity, a progressive increase of miR-34a in visceral adipose tissue is accompanied by a decline in FGF21 sensitivity, leading to hypoadiponectinemia and insulin resistance. The possibility of selective inhibition of miR-34a in the adipose tissue, as a therapeutic approach to obesity-related metabolic disorders, warrants further investigation. Acknowledgement: This work was supported by a grant from the Health & Medical Research Fund (02132836).