Hepatic SerpinA1 improves energy and glucose metabolism through regulation of preadipocyte proliferation and UCP1 expression

Shota Okagawa, Masaji Sakaguchi (), Yuma Okubo, Yuri Takekuma, Motoyuki Igata, Tatsuya Kondo, Naoki Takeda, Kimi Araki, Bruna Brasil Brandao, Wei-Jun Qian, Yu-Hua Tseng, Rohit N. Kulkarni, Naoto Kubota, C. Ronald Kahn and Eiichi Araki
Additional contact information
Shota Okagawa: Kumamoto University, 1-1-1 Honjo
Masaji Sakaguchi: Kumamoto University, 1-1-1 Honjo
Yuma Okubo: Kumamoto University, 1-1-1 Honjo
Yuri Takekuma: Kumamoto University, 1-1-1 Honjo
Motoyuki Igata: Kumamoto University, 1-1-1 Honjo
Tatsuya Kondo: Kumamoto University, 1-1-1 Honjo
Naoki Takeda: Kumamoto University
Kimi Araki: Kumamoto University
Bruna Brasil Brandao: Harvard Medical School
Wei-Jun Qian: Pacific Northwest National Laboratory, Richland
Yu-Hua Tseng: Harvard Medical School
Rohit N. Kulkarni: Harvard Medical School
Naoto Kubota: Kumamoto University, 1-1-1 Honjo
C. Ronald Kahn: Harvard Medical School
Eiichi Araki: Kumamoto University, 1-1-1 Honjo

Nature Communications, 2024, vol. 15, issue 1, 1-19

Abstract: Abstract Lipodystrophy and obesity are associated with insulin resistance and metabolic syndrome accompanied by fat tissue dysregulation. Here, we show that serine protease inhibitor A1 (SerpinA1) expression in the liver is increased during recovery from lipodystrophy caused by the adipocyte-specific loss of insulin signaling in mice. SerpinA1 induces the proliferation of white and brown preadipocytes and increases the expression of uncoupling protein 1 (UCP1) to promote mitochondrial activation in mature white and brown adipocytes. Liver-specific SerpinA1 transgenic mice exhibit increased browning of adipose tissues, leading to increased energy expenditure, reduced adiposity and improved glucose tolerance. Conversely, SerpinA1 knockout mice exhibit decreased adipocyte mitochondrial function, impaired thermogenesis, obesity, and systemic insulin resistance. SerpinA1 forms a complex with the Eph receptor B2 and regulates its downstream signaling in adipocytes. These results demonstrate that SerpinA1 is an important hepatokine that improves obesity, energy expenditure and glucose metabolism by promoting preadipocyte proliferation and activating mitochondrial UCP1 expression in adipocytes.

Date: 2024
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DOI: 10.1038/s41467-024-53835-9

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