Cell cover: Domestic scholars have found that beige fat local hyperthermia may help lose weight

Obesity is a major risk factor for diseases such as diabetes, hypertension, hyperlipidemia, fatty liver, cardiovascular disease and certain cancers, which seriously endangers human health
.

Beige fat is a newly discovered type of fat that exhibits the characteristics of white fat at rest, but has the potential to brown when activated by cold or beta-adrenergic receptor agonists and promote production.

Although cold stimulation or beta-adrenergic agonists are effective methods of activating beige fat, these methods have limited effects in humans and may have potential side effects that can harm your health
.

Therefore, there is an urgent need to discover new targets and strategies to activate beige fat against obesity in a safe and effective manner

On March 5, 2022, Beijing time, researchers Ma Xinran and Xu Lingyan from the School of Life Sciences of East China Normal University, together with Professor Hu Cheng from the Sixth People's Hospital Affiliated to Shanghai Jiaotong University and researcher Zhang Qiang from the School of Life Sciences of East China Normal University, published a paper entitled "Cell".
Paper on "Local Hyperthermia Therapy Induces Browning of White Fat and Treats Obesity"
.

This study reports the effects and molecular mechanisms by which local hyperthermia of beige fat can activate thermogenesis through the HSF1-A2b1 transcriptional axis, reduce obesity and improve metabolic disorders
.

At the same time, the paper was selected as the cover story of Cell, which will be officially published on March 17

Design of the cover paper of the Cell March issue: Local hyperthermia promotes the browning of white fat and improves metabolic health
.

The cover idea is taken from the story of Pheonix (the phoenix from Greek mythology and the legend of Phoenix Nirvana written by Mr.

HSF1 is a classic heat shock transcription factor, traditionally considered to transcriptionally activate the expression of molecular chaperones HSPs to maintain intracellular protein homeostasis under various stress conditions such as heat shock
.

In recent years, HSF1 has been found to have a wider range of physiological functions and regulate target genes

Given the nature of HSF1 being activated under heat shock, the researchers turned to heat therapy
.

As a means of treatment, heat therapy has been around for a long time

Based on the previous research results, Ma Xinran/Xu Lingyan's team focused on beige fat, and cooperated with researcher Zhang Qiang, using beige fat to inject photothermal hydrogel based on polydopamine nanoparticles, and irradiating beige fat under mild temperature (41± 0.
5oC) efficient local hyperthermia
.

Using thermosensitive fluorescent dyes, infrared thermal imaging technology, and HSF1 fat-specific knockout mice, the effects of local hyperthermia on beige fat on adipose tissue and overall metabolism were tested, and it was found that local hyperthermia not only promoted the production of beige fat cells in vitro Heat, topical hyperthermia is also sufficient to activate adipose tissue thermogenesis in mice and humans

Next, in order to further explore and improve the HSF1 metabolic regulatory network, the researchers used ChIP-Seq technology to screen the target genes directly regulated by HSF1 in beige fat on a genome-wide scale, and found that HSF1 may promote the downstream molecule HNRPA2B1 (A2B1) Transcription plays a regulatory role and was validated using AAV adeno-associated virus-mediated beige fat-specific overexpression/knockdown of A2B1 mice and A2B1 knockout mice
.

Further mechanism studies in vitro showed that A2B1 promoted white fat browning and energy metabolism by maintaining the mRNA stability of key metabolic genes Pgc1α, Ucp1, Elovl3, Cytc, etc.

Finally, in order to evaluate the relationship between HSF1 and human metabolic traits, Ma Xinran/Xu Lingyan's research group and Professor Hu Cheng of the Sixth People's Hospital Affiliated to Shanghai Jiaotong University, through the genomic variation analysis of more than 10,000 people, found that the HSF1 mutant p.
Pro365Thr was associated with the population The improved association of multiple metabolic traits, such as lower BMI, serum triglyceride levels, insulin sensitivity, etc.
, and this functional SNP of HSF1 can promote the expression of A2B1 in cells and mice, indicating that HSF1 plays a role in human metabolism It also plays an important role, and therapeutic approaches targeting HSF1-A2B1 will have important clinical implications
.

Schematic diagram of this work (Graphic Abstract)

Overall, this study innovatively found that in addition to cold stimuli, beige fat can sense local mild thermal effects and activate thermogenesis through HSF1, safely and effectively resist and treat obesity and improve metabolic disorders such as insulin resistance and hepatic lipid deposition
.
In addition, this study is the first to discover the HSF1-A2B1 transcriptional axis at the genome level, further improving the HSF1 metabolic regulatory network
.
The association between HSF1 and metabolic traits has been clarified in a study of tens of thousands of people, thus providing a new target and a new strategy for obesity intervention
.

The study was completed with East China Normal University as the first unit and in cooperation with the Sixth People's Hospital Affiliated to Shanghai Jiaotong University
.
Researcher Ma Xinran and Xu Lingyan of East China Normal University, Professor Hu Cheng of the Sixth People's Hospital Affiliated to Shanghai Jiaotong University, and Researcher Zhang Qiang of East China Normal University are the co-corresponding authors of the study, and postdoctoral researcher Li Yu and associate researcher Wang Dongmei of East China Normal University are the co-first authors
.
The research was strongly supported and assisted by researcher Li Dali and Cheng Yiyun of East China Normal University, and researcher Wang Jiqiu of Ruijin Hospital Affiliated to Shanghai Jiaotong University
.

The research was funded by the National Natural Science Foundation of China Youqinghe General Program, the National Key R&D Program, and the Shanghai Science and Technology Commission
.

Attached: Ma Xinran's Research Group of East China Normal University, Hu Cheng's Research Group of the Sixth People's Hospital Affiliated to Shanghai Jiaotong University, and Wang Jiqiu's Research Group of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine are recruiting postdoctoral fellows/research assistants

Ma Xinran's research group mainly focuses on the regulation mechanism of lipid metabolism in fat and liver tissue, and systematically analyzes the maintenance mechanism of key lipid regulatory molecules in the transcriptional/epigenetic regulation level of lipid metabolism homeostasis, as well as the mechanism of obesity and fatty liver development.
influence
.
The research results have been published in Cell, Cell Metab, PNAS, J Hepatol, Hepatology, Cell Res and other journals
.
Postdoctoral application materials should be sent to: xrma@bio.
ecnu.
edu.
cn (East China Normal University)

Starting from the genetic mechanism of type 2 diabetes and its complications, Hu Cheng's research group analyzed the mechanism of new genes involved in the pathogenesis of metabolic diseases through fat, liver, pancreatic islets, and central nervous system
.
Research results have been published in journals such as Cell, Nat Genet, Diabetes, J Clin Invest, J Hepatol,
etc.
Postdoctoral and research assistant application materials should be sent to: alfredhc@sjtu.
edu.
cn (Sixth People's Hospital)

Wang Jiqiu's research group is engaged in the research on the pathogenesis and clinical intervention of obesity.
In recent years, he has focused on the genetics of obesity, the regulation of appetite in the brain and gut, and the direction of nutrient absorption
.
Research results have been published in academic journals such as Nat Med, Nat Cell Biol, Sci Adv, Circulation, Cir Res, Diabetes,
etc.

Related paper information:

https://doi.
org/10.
1016/j.
cell.
2022.
02.
004

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