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11

2024

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09

He Chuan and other teams have shown that METTL14 regulates insulin sensitivity throughout the body through a mechanism independent of UCP1!

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Brown adipose tissue (BAT) regulates systemic metabolism by releasing signaling lipids. N6-Methyl adenosine (m6A) is the most prevalent and abundant post-transcriptional mRNA modification reported to regulate BAT adipogenesis and energy expenditure.

On September 9, 2024, Rohit N. Kulkarni of Harvard Medical School and He Chuan of the University of Chicago in the United StatesCell Metabolism（IF=27.7）Published online entitled“m in brown fat6A mRNA methylation regulates systemic insulin sensitivity independently of UCP1 via the interorgan prostaglandin signaling axis”The research paper,The study showedm in brown fat6A mRNA methylation regulates systemic insulin sensitivity via an interorgan prostaglandin signaling axis independent of UCP1.

Here, the researchers demonstrate that m6Deletion of A methyltransferase-like 14 (METTL14) alters the BAT secretome to improve systemic insulin sensitivity independent of UCP1.Using lipidomics, prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) were identified as insulin sensitizers secreted by BAT. PGE2 and PGF2a inversely correlate with human insulin sensitivity and protect mice from high-fat diet-induced insulin resistance by inhibiting specific AKT phosphatases.Mechanically, METTL14-mediated m6A promotes the decay of genes PTGES2 and CBR1 encoding PGE2 and PGF2a biosynthetic enzymes in brown adipocytes through YTHDF2/3. Consistent, BAT-specific knockdownPtges2orCbr1Reversible M14KOInsulin sensitization in mice.Collectively, these findings reveal a new biological mechanism by which the m6A- dependent regulation of systemic insulin sensitivity.

 

Brown adipose tissue (BAT) has become a potential target for the treatment and prevention of human obesity and related metabolic disorders, which stem from its uncoupling protein 1 (UCP1)-mediated thermogenic function. In humans, BAT-mediated energy expenditure during low-temperature exposure contributes to the reduction of body fat. BAT has also been reported to promote cardiometabolic health, particularly in people who are overweight or obese.Although BAT is traditionally thought to have thermogenic capacity under cold stimulation, it may also provide metabolic benefits through its ability to assist in the utilization of nutrients (e. g., glucose, fatty acids, branched chain amino acids) through the action of secreted factors during energy dissipation.

Notably, BAT has been reported to have a positive effect on systemic metabolism through the secretion of factors including peptides, proteins, lipids or microRNAs.In particular, a class of lipids called "BAT lipid factors" has attracted attention in recent years. The term "lipid factors" was originally defined as lipid hormonal processes secreted by adipose tissue that are involved in systemic metabolism, including the regulation of insulin sensitivity, glucose tolerance and inflammation.For example, 12,13-diHOME, when induced by cold and exercise, enhances fatty acid transport to BAT, reduces circulating triglycerides, and promotes fatty acid uptake by skeletal muscle. 12-HEPE, another cold-induced BAT liptin, stimulates glucose uptake by BAT and muscle.

m 6A is the most common, abundant, and conserved internal post-transcriptional modification of eukaryotic mRNAs. This modification is mainly carried out by the writer complex, which is composed of proteins such as methyltransferase-like 14 (METTL14), methyltransferase-like 3 (METTL3), and Wilms tumor-associated protein 1 (WTAP). m6Removal of A is accomplished by demethylases such as fat mass and obesity-related protein (FTO) or alkB homolog 5 (ALKBH5). m6The effect of A modification on mRNA metabolism largely depends on different m6A interprets the recognition of proteins, thereby regulating mRNA stability, translation, splicing, and/or export.For example, the effect of YTH N(6)-methyladenosine RNA-binding protein 2 (YTHDF2) or YTH N(6)-methyladenosine RNA-binding protein 3 (YTHDF3) on m 6Recognition of A controls the decay of the target mRNA.

In this study, the authors propose to modulate systemic insulin sensitivity METTL14 modulating BAT secretion through a unique mechanism independent of UCP1. BAT-specific Mettl14 knockout (M14KO) mice showed improvements in insulin sensitivity and glucose tolerance, independent of body weight, sex, or standard BAT thermogenesis.Non-targeted lipidomic analysis of mouse BAT and human brown adipocytes (hbat) found that METTL14 lacked secondary up-regulation of prostaglandin E2 (PGE2), prostaglandin D2 (PGD2), prostaglandin F2 alpha (PGF2a), and 13,14-dh-15-keto-PGE2.PGE2 and PGF2a improve whole-body insulin sensitivity by inhibiting AKT phosphatase in key peripheral metabolic tissues. Mechanically, the lack of METTL14 in BAT prevents the decay of PTGES2 and CBR1 transcripts that encode prostaglandin biosynthetic enzymes, allowing their protein levels to increase. M14KO-Interscapular BAT (iBAT)Ptges2orCbr1Down-regulation of the gene reverses the insulin-sensitizing phenotype.Taken together, these results demonstrate a new mechanism for the m6AMethylation is coupled to the BAT secretome to modulate systemic insulin sensitivity independent of the typical BAT thermogenic action.

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