2047-LB: METTL2 Knockout Mitigates Obesity and Metabolic Disorders Induced by High-Fat Diet

Objective: METTL2 is a tRNA methyltransferase primarily accountable for m3C modification of cytoplasmic tRNA. However, the existing comprehension of METTL2 is relatively limited, and the association between METTL2 and metabolic diseases remains undisclosed. This study aims to investigate the role of METTL2 in glucose-lipid metabolism and elucidate its underlying mechanism.

Methods: Studies were conducted in age-matched male METTL2 whole-body knockout (MeKO) and wild-type (WT) mice that fed normal chow (NC) or a high-fat diet (HFD) for 20 weeks. We performed comprehensive longitudinal assessment of body weight, energy balance, glucose homeostasis and global fat deposition. Additionally, we assessed steatohepatitis, adipose hypertrophy and adipose inflammation, and further explored potential mechanism.

Results: In the basal state, MeKO mice exhibited slower weight gain and body length compared to WT mice, although there was no significant difference in glucose homeostasis. In HFD-induced obesity model, MeKO mice showed reduced body weight and fat mass compared to WT mice. This reduction was accompanied by increased energy expenditure, while food intake remained unchanged. As a result, metabolic homeostasis was significantly improved in MeKO mice. METTL2 knockout alleviated the progression of steatohepatitis by inhibiting hepatic fatty acid uptake and synthesis. Furthermore, METTL2 knockout upregulated the expression of the lipolysis molecule ATGL in epididymal white adipose tissue and ameliorated adipose tissue inflammation.

Conclusion: Taken together, these findings suggested that METTL2 represents a novel molecule involved in HFD-induced obesity and associated metabolic disorders.