With the development of the economy and the improvement of people's living standards, obesity is becoming more and more common. According to the World Health Organization, the number of obese people in the world has nearly tripled since 1975. In 2016, more than 650 million adults aged 18 and over were obese globally, accounting for 13%.
Obesity is a health-damaging accumulation of excess fat that can be harmful to people and is not to be underestimated, often leading to metabolic disorders and susceptibility to metabolic diseases, including type 2 diabetes, hepatic steatosis and cardiovascular disease.
As an endocrine organ with pleiotropic function, adipose tissue is divided into white, brown and beige fats according to its anatomical location and metabolic function. Among them, white fat is responsible for storing excess heat energy, and brown fat is combustible fat that can be converted into heat. Beige fats, a newly discovered class of fats, exhibit the qualities of white fats at rest, and have the potential to brown in cold or β adrenaline activation, which can promote thermogenesis and energy expenditure. However, the detailed mechanisms and safety strategies for beige fat activation are unclear.
On March 4, 2022, Researchers Ma Xinran and Xu Lingyan of the Obesity and Metabolic Disease Research Group of the College of Life Sciences of East China Normal University, Professor Hu Cheng, jointly with Professor Hu Cheng, Research Group of Metabolic Disease Genetics, Sixth People's Hospital Affiliated to Shanghai Jiao Tong University, and Zhang Qiang, Researcher Of The Biomass Nanomaterials Research Group of the School of Life Sciences of East China Normal University, jointly published a paper entitled Local hyperthermia therapy induces browning of white in the Journal of Cell Fat and treats obesity research papers.
Studies have found that in addition to cold stimulation, beige fat can sense local mild thermal effects and activate thermogenesis through heat shock transcription factor 1 (HSF1), which can safely and effectively resist and treat obesity, and improve metabolic disorders such as insulin resistance and liver lipid deposition.
Image source: Cell
First, the researchers focused on heat therapy. As a treatment, heat therapy has a long history. Ancient Chinese people have long used drug fumigation, mugwort, fire cans and other methods to treat diseases, and heat therapy technology has a wide range of clinical applications. In recent years, thermal therapies such as saunas, hot yoga, and hot baths have also been shown to improve metabolism to some extent. However, systemic hyperthermia may increase the risk of neurological and cardiovascular disease.
So, are beige fats involved in the metabolic benefits of hyperthermia?
In order to solve the above problems, the study is to safely and effectively activate beige fat by constructing a local heat therapy model in vitro. In vitro, fat cells are placed in a hot environment for two hours. In vivo, a photothermal gel (PDA) composed of polydopamine nanoparticles was injected subcutaneously into the white adipose tissue of the mouse in both groins. When exposed to infrared light, this hydrogel can be precisely heated up according to the target temperature, thus achieving efficient local hyperthermia of beige fat at a mild temperature (41±0.5 °C). These in vitro and in vivo data suggest that local hyperthermia promotes thermogenesis and brown gene programs in beige fat cells in a cellularly autonomous manner.
Next, the researchers explored the long-term effects of chronic local hyperthermia on metabolic performance. A bilateral local hyperthermia model was established, and mice were injected subcutaneously into the white adipose tissue of the bilateral inguinal groove and received a high-fat diet. Subsequently, treatment is treated with NIR laser treatment every 3 days for more than 10 weeks. Tissue analysis showed that chronic hyperthermia mice had significantly smaller fat pools and less lipid accumulation in the liver. And there were no other adverse effects in chronic hyperthermia mice.
Next, the researchers revealed the mechanism by which local hyperthermia activates beige fat. Given the nature of HSF1 being activated under thermal excitation, the researchers constructed HSF1 fat conditioned knockout mice (HSF1 FKO) and performed high-fat feeding. HSF1 FKO mice were found to have increased obesity and reduced energy expenditure.
Topical hyperthermia significantly promotes metabolic improvement, including reduced body weight, fat mass, and fat cell size. However, in HSF1 FKO mice, these metabolic benefits of local hyperthermia were canceled. These results reveal the critical role of HSF1 in mediating the metabolic benefits of local hyperthermia.
To further elucidate the mechanism of HSF1 in regulating beige fat activation, the researchers performed a ChIP-seq analysis and, by ChIP experiments, confirmed the possible presence of HSF1-A2B1 axes after local hyperthermia. Next, the researchers examined the role of A2B1 in beige fat function and found that A2B1 levels were closely related to beige fat function. Functionally, A2B1 knockdown reduces the brown fat gene program in beige fat cells. These results reveal the function of A2B1 in beige fats, and the indispensable role of the HSF1-A2B1 transcription axis in mediating local hyperthermia to activate beige fats.
Finally, in order to reveal its clinical relevance, the association of HSF1 genetic variants (single nucleotide polymorphisms, SNPs) with human metabolic characteristics was explored, and the association of HSF1 variant P365T with human metabolic characteristics was found. The potential contribution of HSF1 in human metabolism was demonstrated, and HSF1 activation may serve as a target for the prevention and treatment of obesity.
Taken together, this study confirms that local hyperthermia induces beige fat activation through the transcription axis HSF1-A2B1, safely and effectively resists and treats obesity, insulin sensitivity and liver lipid deposition, providing a promising anti-obesity strategy.
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[1] Li, Yu, Dongmei Wang, Xiaodan Ping, Yankang Zhang, Ting Zhang, Li Wang, Li Jin et al. "Local hyperthermia therapy induces browning of white fat and treats obesity." Cell (2022).
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