MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes

There is currently a global epidemic of obesity and obesity-related diseases such as type 2 diabetes due to decreased physical activity, excessive food intake, and/or genetic predisposition. The Hippo-YAP1 pathway has attracted attention as a potential therapeutic target because YAP1/TAZ activation in murine immature adipocytes in vitro suppresses their differentiation by inhibiting PPARγ activity. However, the role of YAP1 activation in mature adipocytes in vivo remains unclear. MOB1, whose expression is increased in obesity, is the hub of the Hippo core molecule complex and negatively regulates YAP1/TAZ activation. Therefore, we generated aMob1DKO mutant mice, which feature deficiency of <i>Mob1a/b</i> specifically in mature adipocytes. Compared to controls, aMob1DKO mice subjected to a high-fat diet showed beneficial changes consistent with resistance to diet-induced obesity. The mutants exhibited increases in basal lipolysis, "beiging," and energy expenditure, as well as suppression of ROS production and inflammation in white adipose tissue. Insulin sensitivity and glucose tolerance were improved, and ectopic fat accumulation was reduced. Most of these changes were dependent on the YAP1 activation observed in mature white adipose tissue of aMob1DKO mice. FGF21, which improves lipid metabolism, was upregulated directly via YAP1 activation, and many of the phenotypes seen in aMob1DKO mice were also dependent on FGF21. Thus, the aMob1DKO mouse is an interesting model for the study of the metabolic effects of diet-induced obesity and protection against diabetes. Our work suggests that a YAP1-FGF21 axis exists in adipocytes that may be a potential therapeutic target for obesity.

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Journal
Proceedings of the National Academy of Sciences
Published
2025-04-21
DOI
https://doi.org/10.1073/pnas.2424741122
Citations
2
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
2.30

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article

MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes

Junji Otani, Tomohiko Maehama, Akira Suzuki, Tsutomu Sasaki et al.
2 citations
Proceedings of the National Academy of Sciences
Hippo pathway signaling and YAP/TAZ
2.30
article

MOB1 deletion in murine mature adipocytes ameliorates obesity and diabetes

Junji Otani, Tomohiko Maehama, Akira Suzuki, Tsutomu Sasaki, Hiroki Hikasa, Tomoyoshi Soga, Keiko Yamaguchi, Daisuke Kohno, Masakazu Shinohara, Masashi Oshima, Hiroshi Nishina, Minna Woo, Takehiko Sasaki, Tadahiro Kitamura, Atsuo T. Sasaki, Miki Nishio, K Nakao, Koichi Kawamura, Katsuya Yuguchi
article en
2 citations

Abstract

There is currently a global epidemic of obesity and obesity-related diseases such as type 2 diabetes due to decreased physical activity, excessive food intake, and/or genetic predisposition. The Hippo-YAP1 pathway has attracted attention as a potential therapeutic target because YAP1/TAZ activation in murine immature adipocytes in vitro suppresses their differentiation by inhibiting PPARγ activity. However, the role of YAP1 activation in mature adipocytes in vivo remains unclear. MOB1, whose expression is increased in obesity, is the hub of the Hippo core molecule complex and negatively regulates YAP1/TAZ activation. Therefore, we generated aMob1DKO mutant mice, which feature deficiency of <i>Mob1a/b</i> specifically in mature adipocytes. Compared to controls, aMob1DKO mice subjected to a high-fat diet showed beneficial changes consistent with resistance to diet-induced obesity. The mutants exhibited increases in basal lipolysis, "beiging," and energy expenditure, as well as suppression of ROS production and inflammation in white adipose tissue. Insulin sensitivity and glucose tolerance were improved, and ectopic fat accumulation was reduced. Most of these changes were dependent on the YAP1 activation observed in mature white adipose tissue of aMob1DKO mice. FGF21, which improves lipid metabolism, was upregulated directly via YAP1 activation, and many of the phenotypes seen in aMob1DKO mice were also dependent on FGF21. Thus, the aMob1DKO mouse is an interesting model for the study of the metabolic effects of diet-induced obesity and protection against diabetes. Our work suggests that a YAP1-FGF21 axis exists in adipocytes that may be a potential therapeutic target for obesity.

Proceedings of the National Academy of SciencesVol. 122(17)
SHOWA Medical University (JP), University Health Network (CA), Jichi Medical University (JP), Waseda University (JP), Gunma University (JP), University of Toronto (CA), University of Occupational and Environmental Health Japan (JP), Keio University (JP), Kyoto University (JP), Diabetes Canada (CA), Hiroshima University Hospital (JP), Baptist Hospital (US), Jichi Medical University Hospital (JP), Social Insurance Saitama Chuo Hospital (JP), Quantum Technologies (Sweden) (SE), Kobe University (JP), University of Cincinnati Medical Center (US)
Foundation for the National Institutes of Health, Japan Agency for Medical Research and Development, Ministry of Education, Culture, Sports, Science and Technology, Tokyo Medical and Dental University, Japan Society for the Promotion of Science, Core Research for Evolutional Science and Technology
Good health and well-being
Openalex Percentile: Top 14%
Hippo pathway signaling and YAP/TAZ
2.30
DOIOpen Access PDFOpenAlex
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