The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity
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 tha...
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| creator | Yanagida, Keisuke 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, Takashi Ishii, Satoshi Shimizu, Takao |
| description | 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. |
| doi_str_mv | 10.1172/jci.insight.97293 |
| format | Article |
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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. 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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.</abstract><cop>United States</cop><pub>American Society for Clinical Investigation</pub><pmid>30568036</pmid><doi>10.1172/jci.insight.97293</doi><orcidid>https://orcid.org/0000-0002-2458-3875</orcidid><orcidid>https://orcid.org/0000-0002-9079-1357</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Adipocytes - metabolism Adipogenesis - genetics Adiponectin - metabolism Adipose Tissue - metabolism Adipose Tissue - pathology Adipose Tissue, White - metabolism Animals Diet, High-Fat Disease Models, Animal Fibroblasts Gene Expression Regulation Glucose Tolerance Test GTP-Binding Protein alpha Subunits, G12-G13 - metabolism Insulin - metabolism Insulin Resistance Male Mice Mice, Inbred C57BL Mice, Knockout Mitochondria - metabolism Obesity - genetics Obesity - metabolism Obesity - pathology Phosphorylation PPAR gamma - metabolism Receptors, Purinergic - genetics Receptors, Purinergic - metabolism Signal Transduction Tissue Expansion - methods |
| title | The Gα12/13-coupled receptor LPA4 limits proper adipose tissue expansion and remodeling in diet-induced obesity |
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