Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism

Koo, Ja Hyun; Kim, Tae Hyun; Park, Shi-Young; Joo, Min Sung; Han, Chang Yeob; Choi, Cheol Soo; Kim, Sang Geon

doi:10.1172/jci92067

Cited by 26 publications

(42 citation statements)

References 56 publications

(60 reference statements)

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“…Future studies should identify the LPA receptor(s) and precise mechanisms that mediate LPA-induced muscle insulin resistance. It is possible that G13, a mediator downstream of most LPA receptors (13), plays a role in the inhibition of muscle insulin function by LPA because G13 impairs muscle glucose uptake and systemic insulin sensitivity in high-fat diet-fed mice (45).…”

Section: Discussionmentioning

confidence: 99%

Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

D’Souza

Nzirorera

Cowie

et al. 2018

Journal of Lipid Research

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Autotaxin (ATX) is an adipokine that generates the bioactive lipid, lysophosphatidic acid (LPA). ATX-LPA signaling has been implicated in diet-induced obesity and systemic insulin resistance. However, it remains unclear whether the ATX-LPA pathway influences insulin function and energy metabolism in target tissues, particularly skeletal muscle, the major site of insulin-stimulated glucose disposal. The objective of this study was to test whether the ATX-LPA pathway impacts tissue insulin signaling and mitochondrial metabolism in skeletal muscle during obesity. Male mice with heterozygous ATX deficiency (ATX) were protected from obesity, systemic insulin resistance, and cardiomyocyte dysfunction following high-fat high-sucrose (HFHS) feeding. HFHS-fed ATX mice also had improved insulin-stimulated AKT phosphorylation in white adipose tissue, liver, heart, and skeletal muscle. Preserved insulin-stimulated glucose transport in muscle from HFHS-fed ATX mice was associated with improved mitochondrial pyruvate oxidation in the absence of changes in fat oxidation and ectopic lipid accumulation. Similarly, incubation with LPA decreased insulin-stimulated AKT phosphorylation and mitochondrial energy metabolism in C2C12 myotubes at baseline and following palmitate-induced insulin resistance. Taken together, our results suggest that the ATX-LPA pathway contributes to obesity-induced insulin resistance in metabolically relevant tissues. Our data also suggest that LPA directly impairs skeletal muscle insulin signaling and mitochondrial function.

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Section: Discussionmentioning

confidence: 99%

Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

D’Souza

Nzirorera

Cowie

et al. 2018

Journal of Lipid Research

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“…In all occasions, both Ga 12/13 -and Ga q/11 -induced activation of YAP are largely mediated by RhoA activation. Being the lastly identified among Ga proteins, Ga 12/13 have only recently been implicated to have a role in cellular metabolism (Koo et al, 2017), suggesting another possible link between metabolism and the Hippo pathway. Glucagon and Epinephrine Receptors.…”

Section: Gpcr Ligandsmentioning

confidence: 99%

Interplay between YAP/TAZ and Metabolism

2018

Self Cite

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Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two homologous transcriptional coactivators that promote cell proliferation, stem cell maintenance, and tissue homeostasis. Under favorable conditions, YAP and TAZ are active to promote cell growth through a transcriptional program mediated by the TEAD family transcription factors. Given the indispensability of cellular energy and metabolites for survival and growth, YAP and TAZ are inhibited when energy level is low. Indeed, glucose, fatty acids, hormones, and other metabolic factors have been recently revealed to regulate YAP and TAZ. Conversely, YAP and TAZ are also involved in metabolism regulation, such as to promote glycolysis, lipogenesis, and glutaminolysis, suggesting YAP and TAZ as emerging nodes in coordinating nutrient availability with cell growth and tissue homeostasis. In this Review, we summarize recent findings and provide a current overview of YAP and TAZ in metabolism by focusing on the role of YAP and TAZ as integrators for metabolic cues and cell growth.

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“…For example, hepatic Gα 12 expression is decreased in humans with nonalcoholic fatty liver disease 38 . Hepatic Gα 13 is downregulated 39 , whereas Gα 13 is overexpressed in the skeletal muscle of patients with diabetes 40 . These findings suggest that the balance between Gα 12/13 synthesis and degradation is disrupted under pathological conditions.…”

Section: Degradationmentioning

confidence: 99%

“…The roles of Gα 13 in energy metabolism differ substantially in the skeletal muscle (prodiabetic) and liver (antidiabetic) 39,40 . GNA13 (encoding Gα 13 ) is predominantly expressed in muscles compared with its expression in other metabolically active organs 40 . Exercise diminished Gα 13 expression but increased Gα 12 expression 39 .…”

Section: Role Of Gα 12/13 In Glucose Metabolismmentioning

confidence: 99%

Gα12/13 signaling in metabolic diseases

et al. 2020

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As the key governors of diverse physiological processes, G protein-coupled receptors (GPCRs) have drawn attention as primary targets for several diseases, including diabetes and cardiovascular disease. Heterotrimeric G proteins converge signals from~800 members of the GPCR family. Among the members of the G protein α family, the Gα 12 family members comprising Gα 12 and Gα 13 have been referred to as gep oncogenes. Gα 12/13 levels are altered in metabolic organs, including the liver and muscles, in metabolic diseases. The roles of Gα 12/13 in metabolic diseases have been investigated. In this review, we highlight findings demonstrating Gα 12/13 amplifying or dampening regulators of phenotype changes. We discuss the molecular basis of G protein biology in the context of posttranslational modifications to heterotrimeric G proteins and the cell signaling axis. We also highlight findings providing insights into the organ-specific, metabolic and pathological roles of G proteins in changes associated with specific cells, energy homeostasis, glucose metabolism, liver fibrosis and the immune and cardiovascular systems. This review summarizes the currently available knowledge on the importance of Gα 12/13 in the physiology and pathogenesis of metabolic diseases, which is presented according to the basic understanding of their metabolic actions and underlying cellular and molecular bases. GPCR-G protein pathways in metabolic diseases Metabolic syndrome has been a serious health issue in the 21st century. It is a cluster of risk factors that can lead to cardiovascular diseases, diabetes, and stroke. Insulin resistance is the major factor that induces metabolic syndrome. It has been estimated that 642 million people will have type 2 diabetes by 2040 1. The G protein-coupled receptor (GPCR) family is the largest membrane receptor family and serves as an attractive drug target. Currently, FDA-approved drugs, which account for approximately one-third of all drugs, target more than 100 GPCRs 2. The glucagon-like peptide-1 (GLP-1) receptor, a member of the glucagon receptor family of GPCRs, is a metabolic syndrome-associated drug target. GLP-1 receptor agonists are used for glycemic control in patients with type 2 diabetes mellitus 3. Because of its weight-loss effects, liraglutide (Saxenda TM) has become the first GLP-1 receptor agonist approved for the treatment of obesity 4. Many GPCRs are pivotal sensors of energy metabolism. Some GPCRs are activated by energy metabolites or substrates, such as fatty acids, nucleotides, saccharides, hydroxycarboxylic acids, and citric acid cycle intermediates 5. GPCRs activated by fatty acid-derived lipids have been proposed as antidiabetic drugs 6. For example, the beneficial effect of omega-3 fatty acids is mediated by GPR120, also known as free fatty acid receptor 4. GPR120 is an attractive therapeutic target for the treatment of type 2 diabetes. GPR120-selective agonists improve insulin resistance and chronic inflammation and are currently under investigation for possible drug development...

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Gα13 ablation reprograms myofibers to oxidative phenotype and enhances whole-body metabolism

Cited by 26 publications

References 56 publications

Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

Autotaxin-LPA signaling contributes to obesity-induced insulin resistance in muscle and impairs mitochondrial metabolism

Interplay between YAP/TAZ and Metabolism

Gα12/13 signaling in metabolic diseases

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