Discovery of obesity preventing liver-derived protein by Kumamoto University provides expectation for treatment of diabetes through activation of brown adipose

A research group led by Assistant Professor Masaji Sakaguchi, Research Student Shota Okagawa, Professor Naoto Kubota, and Professor Emeritus Eiichi Araki of the Faculty of Life Sciences at Kumamoto University, has announced their research results showing that "SerpinA1," a liver-derived protein, improves energy metabolism by activating brown adipose tissue and inducing the browning of white adipose (beige adipose). The findings are expected to contribute to developing new obesity and diabetes treatments and were published in the international journal Nature Communications on November 12.

Adipose tissue, which is considered a cause of obesity, is roughly divided into white adipose, which stores lipids and energy, and brown adipose, which consumes energy to maintain body temperature. Obesity causes excessive accumulation of triglycerides in white adipose due to excess energy intake and reduced energy utilization and is a major cause of metabolic disorders such as type 2 diabetes. The presence of brown adipose tissue has recently been reported to be effective in suppressing obesity and insulin resistance, but the detailed mechanisms remained unknown.

In 2017, the research group showed that inducible adipose tissue-specific double knockout of insulin and IGF1 receptors in mature adult mice initially caused loss of adipose tissue and development of metabolic syndrome. However, brown adipocytes were recovered, and metabolism improved during long-term observation. Therefore, in this study, they performed a comprehensive proteomic analysis using serum in the brown adipose recovery phase. As a result, SerpinA1 was identified as a factor that promotes brown adipocyte activation.

This factor is a "hepatokine," a hormone produced in the liver. Its increase in serum was shown to contribute to the regeneration of brown adipose tissue. SerpinA1 is a protein produced mainly in the liver and has previously been known to play an important role in tissue protection by inhibiting proteases such as neutrophil elastase. Treatment of mouse and human brown adipocytes with this factor was shown to increase the UCP1 expression, promote activation of mitochondrial function, and enhance the proliferation and function of brown adipose.

UCP1 is a protein found primarily in brown adipocytes and is located in the inner mitochondrial membrane, which promotes heat production. Improved glucose tolerance, increased UCP1 expression, and enhanced heat production under cold stimulation were observed in liver-specific SerpinA1-overexpressing transgenic mice. Conversely, SerpinA1 knockout mice showed exacerbated glucose tolerance, increased insulin resistance, decreased oxygen uptake, and decreased cold tolerance. Decreased UCP1 expression in brown adipose tissue and a tendency toward obesity with high-fat diet feeding were also observed.

To further investigate the mechanism of action of SerpinA1 on brown adipocytes, a proteomic analysis of binding proteins with SerpinA1 was performed. As a result, they discovered EphB2, a cell surface molecule that interacts with SerpinA1 and plays an important role in development and tissue formation in the nervous, hematopoietic, and other systems. SerpinA1 was shown to promote signaling via EphB2 in a β-adrenergic receptor-independent pathway, regulating UCP1 expression and activating mitochondria.

Sakaguchi said, "In this study, we found that SerpinA1, a protein secreted by the liver, plays an important role in regulating energy metabolism. SerpinA1 is expected to be used in such a manner to increase energy utilization and improve glucose metabolism by the action on brown and white adipose tissues. Moving forward, we will continue our research to develop new treatments for obesity and diabetes using this protein."

Journal Information
Publication: Nature Communications
Title: Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression
DOI: 10.1038/s41467-024-53835-9