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

Okagawa, Shota; Sakaguchi, Masaji; Okubo, Yuma; Takekuma, Yuri; Igata, Motoyuki; Kondo, Tatsuya; Takeda, Naoki; Araki, Kimi; Brandao, Bruna Brasil; Qian, Wei-Jun; Tseng, Yu-Hua; Kulkarni, Rohit N.; Kubota, Naoto; Kahn, C. Ronald; Araki, Eiichi

doi:10.1038/s41467-024-53835-9

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

Journal Article · Tue Nov 12 00:00:00 EST 2024 · Nature Communications

DOI:https://doi.org/10.1038/s41467-024-53835-9· OSTI ID:2543014

Okagawa, Shota ^[1]; ^[1]; Okubo, Yuma ^[1]; Takekuma, Yuri ^[1]; Igata, Motoyuki ^[1]; Kondo, Tatsuya ^[1]; Takeda, Naoki ^[1]; ^[1]; Brandao, Bruna Brasil ^[2]; ^[3]; ^[2]; ^[2]; Kubota, Naoto ^[1]; ^[2]; ^[1]

Kumamoto University (Japan)
Harvard Medical School, Boston, MA (United States)
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

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.

View Accepted Manuscript (DOE)

Research Organization:: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)

Sponsoring Organization:: Japan Agency for Medical Research and Development (AMED); Japan Society for the Promotion of Science (JSPS) KAKENHI; National Institutes of Health (NIH); USDOE

Grant/Contract Number:: AC05-76RL01830

OSTI ID:: 2543014

Report Number(s):: PNNL-SA--193874

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 15; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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60 APPLIED LIFE SCIENCES
UCP1
brown adipocytes
diabetes
metabolic syndrome
mitochondria
obesity
organ crosstalk
preadipocyte
serine protease inhibitor

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

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