The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity
Keisuke Yanagida, Hidemitsu Igarashi, Daisuke Yasuda, Daiki Kobayashi, Takayo Ohto-Nakanishi, Noriyuki Akahoshi, Atsushi Sekiba, Tsudoi Toyoda, Tomoko Ishijima, Yuji Nakai, Nobuhiro Shojima, Naoto Kubota, Keiko Abe, Takashi Kadowaki, Satoshi Ishii, Takao Shimizu
Keisuke Yanagida, Hidemitsu Igarashi, Daisuke Yasuda, Daiki Kobayashi, Takayo Ohto-Nakanishi, Noriyuki Akahoshi, Atsushi Sekiba, Tsudoi Toyoda, Tomoko Ishijima, Yuji Nakai, Nobuhiro Shojima, Naoto Kubota, Keiko Abe, Takashi Kadowaki, Satoshi Ishii, Takao Shimizu
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Research Article Metabolism

The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity

Abstract

White adipose tissue (WAT) can dynamically expand and remodel through adipocyte hypertrophy and hyperplasia. The relative contribution of these 2 mechanisms to WAT expansion is a critical determinant of WAT function and dysfunction in obesity. However, little is known about the signaling systems that determine the mechanisms of WAT expansion. Here, we show that the GPCR LPA4 selectively activates Gα12/13 proteins in adipocytes and limits continuous remodeling and healthy expansion of WAT. LPA4-KO mice showed enhanced expression of mitochondrial and adipogenesis genes and reduced levels of inhibitory phosphorylation of PPARγ in WAT, along with increased production of adiponectin. Furthermore, LPA4-KO mice showed metabolically healthy obese phenotypes in a diet-induced obesity model, with continuous WAT expansion, as well as protection from WAT inflammation, hepatosteatosis, and insulin resistance. These findings unravel a potentially new signaling system that underlies WAT plasticity and expandability, providing a promising therapeutic approach for obesity-related metabolic disorders.

Authors

Keisuke Yanagida, Hidemitsu Igarashi, Daisuke Yasuda, Daiki Kobayashi, Takayo Ohto-Nakanishi, Noriyuki Akahoshi, Atsushi Sekiba, Tsudoi Toyoda, Tomoko Ishijima, Yuji Nakai, Nobuhiro Shojima, Naoto Kubota, Keiko Abe, Takashi Kadowaki, Satoshi Ishii, Takao Shimizu

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Figure 5

LPA4 ablation results in enhanced adipose tissue expandability and protection from hepatosteatosis and insulin resistance in a diet-induced obesity model.

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LPA4 ablation results in enhanced adipose tissue expandability and prote...
(A–D) Whole body (A), epididymal white adipose tissue (eWAT) (B), inguinal WAT (iWAT) (C), and liver (D) weight of high-fat diet–fed (HFD-fed) WT (n = 42–52) and Lpar4-KO mice (n = 25–44). (E) Triglyceride (TG) content of the liver from HFD-fed WT and Lpar4-KO mice (n = 6 each). (F) Representative Oil Red O staining of liver sections from HFD-fed WT and Lpar4-KO mice. Scale bar: 100 μm. (G and I) Serum alanine transaminase (ALT) (G), aspartate transaminase (AST) (H), and alkaline phosphatase (ALP) (I) activities of HFD-fed WT and Lpar4-KO mice (n = 8–10). (J) A representative photograph of livers and eWATs from HFD-fed WT and Lpar4-KO mice. (K) Inverse correlation between eWAT and liver weight from HFD-fed WT (n = 52) and Lpar4-KO (n = 39) mice. (L–N) Blood glucose (L and N) and plasma insulin (M) levels of HFD-fed WT (n = 22–24) and Lpar4-KO (n = 20–21) mice during the oral glucose-tolerance test (L and M) and the insulin-tolerance test (N). Each symbol represents an individual mouse. Data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001; unpaired Student’s t test (A–E, G–I) or 1-way ANOVA with Bonferroni’s post hoc test (L–N) were used.