Intermittent hypoxia-induced METTL3 downregulation facilitates MGLL-mediated lipolysis of adipocytes in OSAS

Abstract

Intermittent hypoxia (IH) is the core pathological feature of obstructive sleep apnea syndrome (OSAS), and insulin resistance (IR) is the most common metabolic complication of OSAS. Studies have shown that the levels of free fatty acids (FFAs), which are mainly released from adipocytes by lipolysis, are elevated in OSAS and play an important role in the development of IR. However, whether and how IH regulates adipocyte lipolysis in OSAS is not clear. Here, we revealed that the apnea hypopnea index was positively correlated with the serum levels of FFAs and FFA release from adipocytes in OSAS. In addition, IH facilitated lipolysis and FFA release from adipocytes by downregulating the level of METTL3. METTL3 downregulation impaired N6-methyladenosine (m6A) levels in MGLL mRNA and reduced MGLL expression, thereby promoting lipolysis. In addition, we identified YTHDF2 as the m6A reader that interacts with MGLL mRNA, accelerating its degradation. Furthermore, our data showed reduced levels of METTL3 and elevated levels of MGLL in the adipose tissues of OSAS patients and indicated an effect of METTL3 on lowering FFA levels and improving IR in rats with chronic IH. In conclusion, our study provides new insights into the development and treatment of IR in OSAS.

Update on N6‐methyladenosine methylation in obesity‐related diseases

“…METTL3 inhibited inflammation-induced chondrocyte apoptosis and autophagy through the m6A/YTHDF1/Bcl2 signaling pathway [77]. mRNA through the downregulation of METTL3 [78]. Moreover, OSA is significantly correlated with the development of lung carcinoma.…”

“…Furthermore, patients with severe OSA showed dysregulated expression levels of m6A regulators, including HNRNPA2B1, KIAA1429, ALKBH5, YTHDF2, FMR1, IGF2BP1, and IGF2BP3 [97]. IH is a major feature of OSA that promotes lipolysis and the release of FFAs by significantly reducing the levels of m6A‐modified monoacylglycerol lipase (MGLL) mRNA through the downregulation of METTL3 [78]. Moreover, OSA is significantly correlated with the development of lung carcinoma.…”

N6-methyladenosine RNA modification: an emerging molecule in type 2 diabetes metabolism

“…An in vitro experiment showed that large lipid droplets accumulate in Mettl3-knockout cells via suppression of the mRNA and protein expression of uncoupling protein 1 (UCP1), PPARG coactivator 1 alpha (PCG-1a/PPARGC1A), PPARg, and PR/ SET domain 16 (PRDM16). A recent study on IR in obstructive sleep apnea syndrome showed that downregulation of Mettl3 increased the TG levels, which released FFAs, upregulated glycerol, inhibited glucose utilization in the other organs, and induced IR (60). Since the IR induced by obstructive sleep apnea syndrome is similar to the IR pathogenesis in T2D, this study was included in our review.…”