<jats:title>Abstract</jats:title><jats:p>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<jats:sub>12</jats:sub> family members comprising Gα<jats:sub>12</jats:sub> and Gα<jats:sub>13</jats:sub> have been referred to as <jats:italic>gep</jats:italic> oncogenes. Gα<jats:sub>12/13</jats:sub> levels are altered in metabolic organs, including the liver and muscles, in metabolic diseases. The roles of Gα<jats:sub>12/13</jats:sub> in metabolic diseases have been investigated. In this review, we highlight findings demonstrating Gα<jats:sub>12/13</jats:sub> 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<jats:sub>12/13</jats:sub> 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.</jats:p>