A research group led by Professor Juro Sakai from Tohoku University School of Medicine and Professor Yoshihiro Matsumura from Akita University Graduate School of Medicine announced that they have clarified that the histone demethylase "JMJD1A," which is activated by glucose metabolism, creates new adipocytes. They found that activation of JMJD1A rewrites the epigenome and turns on gene clusters necessary for the differentiation of new adipocytes. This is expected to lead to prevention and treatment methods for obesity and diabetes. The results were published in the online edition of Cell Reports on July 26.
The "me" in the figure denotes dimethylation of the ninth lysine residue of histone H3 protein. Excess glucose increases α-ketoglutarate (αKG) within the nucleus, activating JMJD1A. Activated JMJD1A promotes the regulatory mechanisms shown in (i) to (iv). These mechanisms are amplified in a feedforward manner, thereby promoting the production of new fat cells in visceral adipose tissue. Furthermore, JMJD1A localizes to target genes via another transcription factor (NFIC).
Provided by Tohoku University
Adipocytes have the role of storing surplus energy after meals and supplying it during hunger, but obesity caused by excessive nutrient intake contributes to the development of lifestyle diseases such as type 2 diabetes. Excessive nutrition causes either hypertrophy, where existing adipocytes become larger, or hyperplasia, where new adipocytes are created. Hyperplasia is considered a metabolically favorable adaptive response that maintains metabolic balance and suppresses inflammation and diabetes risk. However, the detailed control mechanisms were not understood.
In this study, the research group focused on the process of differentiation from preadipocytes to adipocytes. They employed metabolome, transcriptome, and epigenome (genetic information that can be rewritten post-developmentally) analyses. By combining these with metabolite imaging, they analyzed these interactions in detail.
As a result, they revealed that when excessive glucose is metabolized intracellularly through glycolysis and the citric acid cycle, the activation factor for the histone demethylase (α-KG: α-ketoglutarate) increases and becomes activated within the nucleus.
They discovered that activated JMJD1A rewrites the epigenome and localizes to genes targeted by a transcription factor (ChREBP), thereby turning on the switches for gene clusters necessary for adipocyte differentiation, and new adipocytes are created from preadipocytes.
Additionally, analysis using mice confirmed that when JMJD1A is deficient in wild-type mice, hyperplasia of adipose tissue does not occur when nutrients are excessively consumed, existing adipocytes become excessively hypertrophic, and inflammation progresses.
Sakai commented: "We have identified the mechanism by which glucose causes the formation of adipocytes. Although it seems paradoxical at first glance, the enzyme JMJD1A holds the key to protecting the health of adipose tissue not by accumulating fat, but by newly creating 'young adipocytes.' Adipocytes do not simply become larger but maintain metabolic balance while being renewed. I believe that understanding this mechanism of 'generational change of fat' will lead to new prevention and treatment strategies for obesity and diabetes."
Journal Information
Publication: Cell Reports
Title: Glucose-activated JMJD1A drives visceral adipogenesis via α-ketoglutarate-dependent chromatin remodeling
DOI: 10.1016/j.celrep.2025.116060
This article has been translated by JST with permission from The Science News Ltd. (https://sci-news.co.jp/). Unauthorized reproduction of the article and photographs is prohibited.