The latest paper from Xiamen University: A new mechanism of adaptive thermogenesis mediated by beige adipose tissue under long-term cold stimulation

Adaptive thermogenesis is a metabolic thermogenic mechanism of the body to external stimuli, which plays an important role in regulating energy homeostasis and is essential
for maintaining body temperature and promoting the survival of animals in cold environments.
Brown and beige adipose tissues are the main tissues
of non-trembling thermogenesis.
The thermogenic activity of brown and beige adipocytes is mainly dependent on Uncoupling protein 1 (UCP1).

UCP1 is a protein located on the inner mitochondrial membrane that generates heat
by dissipating the proton gradient created by the electron transport chain.
High expression of UCP1 is necessary to
maintain high thermogenic activity of brown or beige adipocytes.
Cold stimulation can activate the β3-adrenergic receptors of brown and beige adipocytes by activating sympathetic secretory epinephrine, activate the adrenergic signaling pathway, and promote the transcriptional regulation
of heat-producing genes such as Ucp1 by PPARγ and its co-regulators.
Decreased adaptive thermogenesis dependent on adrenergic activation leads to predisposition to obesity
.
Therefore, promoting thermogenesis may be an effective way to
control obesity.

Beige adipocytes are "brown-like" cells that form in white fat after birth in mammals in response to various external stimuli such as prolonged cold stimuli
.
Beige adipocytes have the form of multilocular small fat droplets, dense mitochondria, high UCP1 expression and strong
thermogenic ability.
Activation of beige adipose tissue significantly promotes whole-body energy expenditure
.
Obesity and associated metabolic disorders
can be observed in mice lacking beige adipocytes.
However, the regulatory mechanism of beige fat development and functional maintenance needs to be further elucidated
.

SOX4 is an important developmental transcription factor
that regulates stem cell properties, differentiation, and multiple developmental pathways.
Recently, the team of Professor Li Boan and Assistant Professor Guo Huiling of the School of Life Sciences of Xiamen University published a paper in Theranostics, and found that SOX4 can promote beige fat cell-mediated adaptive thermogenesis
by promoting the formation of PRDM16-PPARγ complex under long-term cold stimulation.

The experimental group found that after long-term cold stimulation of mice, SOX4 was significantly upregulated
in subcutaneous adipose tissue.
Mice with adipocytes or brown adipocytes specifically knocking out SOX4 showed significant cold intolerance, reduced energy expenditure, reduced beige adipocytes formation, and significantly reduced
expression of associated thermogenic genes such as Ucp1 genes.
In addition, these mice were more likely to develop obesity on a high-fat diet, accompanied by severe hepatic steatosis, insulin resistance, and inflammation
.
At the cellular level, the deletion of pre-adipocytes SOX4 can inhibit the development of beige adipocytes, and knocking down SOX4 in mature beige adipocytes significantly reduces the expression of thermogenic genes and energy metabolism
.
Pref1-SOX4-specific transgenic mice (Pref1-Sox4) specifically expressed by preadipocyte were significantly higher in thermogenesis than wild-type mice under high-fat feeding, and showed resistance
to high-fat-induced obesity.
Through RNA-seq, ChIP-qPCR, FAIRE assay and other experimental analysis, it was found that SOX4 dependence binds to PPARγ, recruits PRDM16, forms a transcriptional complex to drive the expression of heat-producing genes such as Ucp1 to promote heat production, and has important physiological significance
for resisting cold and obesity.

Huanming Shen, Ting He, Shuai Wang, and Lingfeng Hou, Ph.
D.
students from the School of Life Sciences, Xiamen University, are the co-first authors of the paper, and Professor Boan Li and Assistant Professor Guo Huiling are the co-corresponding authors
of the paper.
This project was supported
by the National Key Research and Development Program of China (2020YFA0112300), the National Natural Science Foundation of China (81972458, 32071150), and the Fujian Provincial Health Education Joint Research Project (2019-WJ-34).

Paper link: class="vsbcontent_end" _msthash="101744" _msttexthash="978393">(Photo/text Li Boan's research group)