Leptin Reduces Plin5 m6A Methylation through FTO to Regulate Lipolysis in Piglets

Abstract

Perilipin5 (Plin5) is a scaffold protein that plays an important role in lipid droplets (LD) formation, but the regulatory effect of leptin on it is unclear. Our study aimed to explore the underlying mechanisms by which leptin reduces the N6-methyladenosine (m6A) methylation of Plin5 through fat mass and obesity associated genes (FTO) and regulates the lipolysis. To this end, 24 Landrace male piglets (7.73 ± 0.38 kg) were randomly sorted into two groups, either a control group (Control, n = 12) or a 1 mg/kg leptin recombinant protein treatment group (Leptin, n = 12). After 4 weeks of treatment, the results showed that leptin treatment group had lower body weight, body fat percentage and blood lipid levels, but the levels of Plin5 mRNA and protein increased significantly in adipose tissue (p < 0.05). Leptin promotes the up-regulation of FTO expression level in vitro, which in turn leads to the decrease of Plin5 M6A methylation (p < 0.05). In in vitro porcine adipocytes, overexpression of FTO aggravated the decrease of M6A methylation and increased the expression of Plin5 protein, while the interference fragment of FTO reversed the decrease of m6A methylation (p < 0.05). Finally, the overexpression in vitro of Plin5 significantly reduces the size of LD, promotes the metabolism of triglycerides and the operation of the mitochondrial respiratory chain, and increases thermogenesis. This study clarified that leptin can regulate Plin5 M6A methylation by promoting FTO to affect the lipid metabolism and energy consumption, providing a theoretical basis for treating diseases related to obesity.

Lipid-Independent Regulation of PLIN5 via IL-6 through the JAK/STAT3 Axis in Hep3B Cells

“…In line with this hypothesis, the JAK inhibitor Ruxolitinib and the STAT3 phosphorylation inhibitor STATTIC both inhibited PLIN5 upregulation. This finding confirms previous reports showing PLIN5 being regulated by the JAK/STAT3 pathway after leptin treatment in adipocytes [ 46 , 47 ]. Therefore, we concluded that the JAK/STAT3 signaling axis mediates PLIN5 expression upon IL-6 stimulation in Hep3B.…”

The emergent role of mitochondrial RNA modifications in metabolic alterations

“…These results highlighted the effect of specific DHA‐diet in mitochondrial biogenesis and skeletal muscle fiber via Fto /m 6 A, protecting against obesity‐induced decline in skeletal muscle function (W. Chen et al, 2022). Similarly, Wei et al (2021) treated male piglets with 1 mg/kg of leptin recombinant protein. After 4 weeks treatment, the authors found an upregulation of FTO , which in turn leads to the decrease of m 6 A methylation of mRNA Plin5 .…”

“…An additional in vitro porcine found that overexpression of FTO decreased mRNA m 6 A methylation and increased the expression of Plin5 protein in adipocytes. The overexpression in vitro of Plin5 significantly reduces the size of lipid droplets, promotes the metabolism of triglycerides, and the operation of the mitochondrial respiratory chain, and increases thermogenesis, indicating that Plin5 m 6 A methylation through FTO affects lipid metabolism and energy consumption, providing a new preventive mechanism against obesity (D. Wei et al, 2021). Therefore, these studies can conclude that FTO is responsible for mt‐mRNA modifications that regulate mitochondrial biogenesis in adipose tissue and specifically, lipid metabolism and energy expenditure in obesity.…”

Transcriptome Analysis Reveals the Age-Related Developmental Dynamics Pattern of the Longissimus Dorsi Muscle in Ningxiang Pigs

“…In caponized chickens with low cellular lipid content, RXRG mRNA levels were significantly downregulated [39]. PLIN5 (Perilipin 5), a scaffolding protein, plays an important role in the formation of lipid droplets [40]. IMF is stored in lipid droplets, and overexpression of PLIN5 in vitro could significantly reduce the size of lipid droplets, promote the metabolism of triglycerides and the mitochondrial respiratory chain, and enhance thermogenesis.…”