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

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

doi:10.1172/jci.insight.97293

Cited by 25 publications

(24 citation statements)

References 47 publications

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“…Consis-HUVECs endogenously expressed LPA1, LPA4, and LPA6 mRNA ( Figure 3A). We performed a serum response factor response element (SRF-RE) luciferase reporter assay, which detects the activation of the Gα12/Gα13-Rho-ROCK signaling pathway (38,39). LPA increased the reporter activity, which was abolished by the ROCK inhibitor Y27632 and the siRNA-mediated knockdown of LPA4 and/or LPA6 but not by the LPA1/LPA3 antagonist Ki16425 (ref.…”

Section: Resultsmentioning

confidence: 99%

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

Yasuda

Kobayashi

Akahoshi

et al. 2019

Journal of Clinical Investigation

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al cooperation between LPA4 and LPA6 is essential for embryonic development. Since Lpa4;Lpa5-DKO and Lpa5;Lpa6-DKO mice were born at the expected Mendelian ratios and had no obvious abnormalities (Supplemental Tables 4 and 5), LPA5 is unlikely to be involved in embryonic development. To examine the roles of LPA4 and LPA6 in embryonic development, yolk sac and embryo proper were observed at various stages of gestation. At E8.5, both Lpa4;Lpa6-DKO yolk sac and embryo proper appeared normal (Supplemental Figure 1, A and B). However, at E9.5-10.5, almost all of Lpa4;Lpa6-DKO embryos proper had various morphological abnormalities, such as severe pericardial effusion (Figure 1A and Supplemental Figure 1, B-D), axial turning abnormality (Supplemental Figure 1, B, E, and F), and developmental delay (Figure 1, A and B, and Supplemental Figure 1, B, G, and H). DKO yolk sacs lacked large blood vessels at E9.5-10.5, whereas WT yolk sacs had well-developed blood vessels (Figure 1B and Supplemental Figure 1, A, I, and J). We observed that all DKO embryos died by E11.5 (Supplemental Figure 1, B, K, and L, and Supplemental Table 6). Histological analysis showed that the endoderm and mesoderm of the yolk sacs were more widely separated in the DKO tissue (Figure 1C). Despite this vascular defect, erythrocytes were present in Lpa4;Lpa6-DKO yolk sacs (Figure 1C). Blood vessel-stained whole-mount embryos at E10.5 revealed that DKO embryos had enlarged dorsal aortae and poor vascular networks in the head and intersomitic regions, compared with WT embryos (Figure 1D). Furthermore, blood vessel-stained cross sections of embryos at E9.5 also revealed that DKO embryos had enlarged dorsal aortae and thinned neural tubes, compared with WT embryos (Figure 1E). These results strongly suggest that both LPA4 and LPA6 are indispensable for embryonic angiogenesis. Endothelial LPA4 and LPA6 are involved in retinal angiogenesis. Previously, we detected mRNA expression of Lpa4 and LPA6 in vascular ECs (8, 16). To investigate the functional roles of endothelial LPA4 and LPA6, we generated a tamoxifen-inducible and EC-specific Lpa4/Lpa6 deletion mouse line by crossing Lpa4;Lpa6 double-floxed mutants with transgenic mice carrying Cdh5-CreER T2 (ref. 37, Figure 2A, and Supplemental Figure 2A). The resulting Lpa4 fl/fl(Y) Lpa6 fl/fl Cdh5-CreER T2 mice (termed hereafter Lpa4; Lpa6 iΔEC) were treated with tamoxifen from P1 to P3. Allele-specific PCR confirmed recombination of both floxed alleles in the tails of Lpa4;Lpa6 iΔEC mice at P5 (Supplemental Figure 2B). At P5, we found that the radial expansion, EC area, and retinal blood vessel branching were significantly reduced in Lpa4;Lpa6 iΔEC mice compared with those in control CreER T2-negative Lpa4 fl/fl(Y) ;Lpa6 fl/fl littermates (Figure 2, C and F-H). At the angiogenic front, sprouts of retinal vessels were significantly reduced in Lpa4;Lpa6 iΔEC retina (Figure 2, D and I). Additionally, both the number and length of sprouting filopodia were significantly reduced in Lpa4;Lpa6 iΔEC retina (Figure 2, E, J...

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Section: Resultsmentioning

confidence: 99%

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

Yasuda

Kobayashi

Akahoshi

et al. 2019

Journal of Clinical Investigation

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“…PAFR -/mice are protected against WAT inflammation and exhibit improved insulin sensitivity, albeit with increased adiposity and without any change in calorie intake (65). Thus, the phenotype of PAFR -/mice, similarly to mice lacking leptin while overexpressing adiponectin (66) or other mouse models (67)(68)(69), illustrates the beneficial impact of limiting local inflammation while maintaining storage capacity in the adipose tissue. This increase or maintenance of storage capacity limits ectopic fat deposition and insulin resistance, as well as related complications.…”

Section: Loss Of Adipose Tissue Plasticity In Obesitymentioning

confidence: 98%

Deciphering the cellular interplays underlying obesity-induced adipose tissue fibrosis

Marcelin

Silveira

Martins

et al. 2019

Journal of Clinical Investigation

172

150

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“…These data provide new insight into the potential relative significance of individual LPAR within specific adipose depots, and suggest that further study of LPAR 4, 5, and 6 is warranted. Mice deficient in Lpar1‐5 have been generated (Contos et al, ; Dusaulcy et al, ; Igarashi et al, ; Lin et al, ; Ye et al, ), but an adipose phenotype has only been characterized for Lpar1 (Dusaulcy et al, , ) and Lpar4 knockouts (Yanagida et al, ). Our data in Fig.…”

Section: Resultsmentioning

confidence: 99%

Relative expression and regulation by short‐term fasting of lysophosphatidic acid receptors and autotaxin in white and brown adipose tissue depots

M’Hiri

Silva

Duncan

2020

Lipids

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Lysophosphatidic acid (lysoPtdOH) levels have previously been reported to decrease in rodents with shortterm fasting. We investigated whether a 16 h fast would change expression of autotaxin, the predominant phospholipase D responsible for adipose-derived lysoPtdOH synthesis, or any of the lysophosphatidic acid receptors (1-6) in four white adipose tissue (WAT) depots and interscapular brown adipose tissue (BAT) in male C57Bl/6J mice fed ad libitum, or fasted for 16 h. Aside from small inductions of Lpar1 in epididymal WAT and Lpar2 in epididymal and inguinal WAT, no significant changes were observed in expression of the Lpar family members, or autotaxin in perirenal, retroperitoneal, epididymal, or inguinal WAT or BAT with fasting. Comparison of the relative expression of Lpar1-6 in various depots showed that Lpar6 was the predominant Lpar in both WAT and BAT, and suggests that further work on the adipose-specific role of Lpar6 is warranted.

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

Cited by 25 publications

References 47 publications

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

Lysophosphatidic acid–induced YAP/TAZ activation promotes developmental angiogenesis by repressing Notch ligand Dll4

Deciphering the cellular interplays underlying obesity-induced adipose tissue fibrosis

Relative expression and regulation by short‐term fasting of lysophosphatidic acid receptors and autotaxin in white and brown adipose tissue depots

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