Mogroside V Promotes Brown Adipose Thermogenesis via FTO-m⁶A-LETMD1-UCP1 Pathway to Combat Obesity

Obesity is a chronic, recurrent, and progressive disease caused by energy imbalance. N⁶-methyladenosine (m⁶A) modification regulates fat thermogenesis, potentially counteracting obesity. Mogroside V (MV) is a triterpene glycoside extracted from Siraitia grosvenorii and has shown beneficial effects in models of obesity. However, its underlying mechanism remains unknown. The objective of this study is to investigate the effects of MV on adipose thermogenesis and explore the mechanism of m⁶A modifications in mediating these effects. Mitochondrial respiration analysis, histological and molecular biological methods were used to investigate the thermogenesis in differentiated C3H10T1/2 brown adipocytes and adipose tissue in high-fat diet (HFD)-fed mouse models, respectively. Stable cell models with overexpression or knockdown of fat mass and obesity-associated protein (FTO) were generated to investigate the effects of FTO on m⁶A modification and thermogenesis in brown adipocytes. Methylated RNA immunoprecipitation-quantitative-PCR (MeRIP-qPCR) and RIP-qPCR analysis were used to reveal the potential downstream molecular targets of FTO. MV improved HFD-induced obesity and metabolic dysfunction in mice. MV also increased uncoupling protein 1 (UCP1) expression in brown adipose tissue and enhanced mitochondrial respiration and expression of peroxisome proliferator activated receptor γ coactivator 1α (PGC1α) and UCP1 in differentiated C3H10T1/2 cells. Further analysis of the relevant molecular mechanisms showed that MV suppressed FTO expression, thereby increasing m⁶A modification of LETM1 domain-containing protein 1 (Letmd1) mRNA. The m⁶A-modified Letmd1 transcript was recognized by the m⁶A reader YTH domain-containing protein 2 (YTHDC2), thereby increasing the stability of Letmd1 mRNA. The increased Letmd1 mRNA levels were correlated with increased LETMD1 protein abundance, which subsequently enhanced the expression of PGC1α and UCP1, ultimately promoting brown adipocyte thermogenesis. MV promoted brown adipocyte thermogenesis through the FTO-m⁶A-LETMD1-UCP1 axis, suggesting a potential therapeutic strategy for obesity.