Diabetes and atherosclerosis are paralleled by

Diabetes and atherosclerosis are paralleled by impaired wound healing and endothelial angiogenesis in the periphery, which cause severe complications and mainly occur as a result of the elevated circulating levels of glucose and free fatty acids. Yuan et al. recently showed that palmitic Ch 55 induces such impaired endothelial function through increased MST1 and the consequent inactivation and nuclear exclusion of YAP [34]. Elevated palmitic acid induces mitochondrial damage in human aortic endothelial cells because mitochondrial DNA was found in the cytoplasm where it activated signaling by the cytosolic DNA sensor cGAS–STING–IRF3. Free IRF3 directly binds to the MST1 promoter to induce MST1 expression. Because in this study only a single elevated fatty acid was used as the metabolic stressor, one should not immediately generalize this as a disease mechanism. Nevertheless, it is possible that the constitutively ‘ON’ state of the Hippo pathway by overnutrition, and leading to elevated levels of active MST1, is also a possible mediator of impaired angiogenesis and wound healing in diabetes. In summary, several recent in vivo and in vitro studies show a causative upregulation of the Hippo central kinase MST1 in diabetic cardiomyopathy, diabetic coronary microvascular dysfunction, and atherosclerosis progression, and thus the Hippo pathway could be a strong target for severe macrovascular diabetes complications; however, care must be taken to create selective and balanced compounds.
Concluding Remarks and Future Perspectives A link between the Hippo pathway and metabolism has become increasingly evident according to findings from several different animal and cellular model systems in the past few years. This suggests that the Hippo pathway is not only a growth regulator but also has key functions in the regulation of both cellular and whole-body metabolism, and this establishes Hippo as a novel framework by which cells/organs can coordinate nutrient metabolism with growth, repair, and regenerative processes. Hippo pathway deregulation participates in the pathogenesis of several metabolic diseases such as T2D, fatty liver, and cardiovascular disorders. Of note, novel small-molecule activators/inhibitors that modulate Hippo pathway components are in development 36, 100, 101 and can be exploited for therapeutic approaches in diverse metabolic diseases; for example, MST1 inhibitors have potential for targeting pancreatic β cell failure in diabetes or for promoting the repair and regeneration of damaged cardiac and liver cells. The previous sections summarized and discussed the emerging functions of the Hippo pathway in cellular and whole-body metabolism in pancreas, liver, adipose, and heart, and especially its regulation of energy metabolism and metabolic disease. Beyond those organs, several other systems prominently regulate lipid and glucose metabolism, such as the hypothalamus, skeletal muscle, gastrointestinal tract, and the immune system. In these cases the functional role of Hippo pathway components remains to be clarified. For example, an accelerated immune response with immune cell infiltration and hyperproduction of proinflammatory cytokines contributes to the pathogenesis of metabolic diseases such as T2D. The Hippo pathway also seems to participate in the regulation of both the innate and adaptive immune systems 102, 103, 104, 105, 106, and one can hypothesize that there is a direct link between Hippo pathway dysregulation and inflammation in metabolic disorders. Overall glucose and energy homeostasis is established through complex metabolic pathways – insulin secretion, glucose uptake and metabolism, thermogenesis, mitochondrial function, and autophagy. Further investigation of the consequences of Hippo activation in insulin-sensitive tissues and its cross-communication with other metabolic pathways such as mTOR, AMPK, NOTCH, and insulin is needed. Despite major advances in the Hippo field, our understanding of how the Hippo/metabolism interplay at the cellular level translates into the control of systemic metabolism under physiological and pathophysiological conditions is still at an early stage, and many outstanding questions need to be answered (see Outstanding Questions).