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...

BackgroundMultiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) remain unclear.MethodsTo determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8+ TILs in Il17a−/− mice, Il17aCreR26DTA mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4+ T cells or CD11b+Gr-1hi myeloid cells in vivo, respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset.ResultsDepletion of CD4+ T cells promotes the exhaustion of CD8+ T cells with a concomitant increase in IL-17-producing CD8+ T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8+ T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103+KLRG1−IL-7Rαhi tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1hiTim3+TOX+ terminally exhausted CD8+ T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8+ T cells and also delays tumor growth in vivo. Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8+ T cell exhaustion signature gene sets in multiple cancers.ConclusionIL-17-producing cells promote terminal exhaustion of CD8+ T cells and tumor progression in vivo, which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8+ T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.