br Obesity tips to a systematic failure

Obesity tips to a systematic failure in the overall metabolic regulation; it is a major global health problem and is linked to several metabolic diseases such as (T2D) (see ), (NAFLD), and cardiovascular disorders. The prevalence of such metabolic disorders has increased dramatically worldwide , , , , . For instance, with an estimated number of over 420 million affected people and dramatic increases all over the world, diabetes has already gained epidemic status . Although they share common molecular pathogenic signatures such as chronic low-grade inflammation , the underlying signaling pathways and molecular mechanisms are incompletely understood. Metabolism is a highly coordinated cellular function that can be flexibly regulated by signaling pathways to meet cellular requirements. Given the varied and enigmatic nature of the metabolic regulatory pathways, and the cellular and molecular causes of their dysregulation, the identification of signaling pathways that regulate the activity or expression of specific metabolic genes or pathways in general, together with an in depth-knowledge of their mechanisms of action underlying disrupted metabolic homeostasis in metabolic diseases, is of paramount importance and is urgently needed both for better understanding of disease pathogenesis and for the development of effective therapeutic interventions. First discovered using genetic screens in and subsequently established in mammals, the Hippo pathway has emerged as a key signal that controls organ size and tissue homeostasis by regulating cellular proliferation, survival, and regeneration . Of particular interest is the emerging role of the Hippo pathway in the regulation of metabolic homeostasis at both the cellular and systematic levels. In addition to the pancreas and , , , , , , , , , multiple lines of evidence have uncovered the importance of Hippo signaling components such as MST, LATS, and YAP in cellular glucose and lipid metabolism, as well as in stress and metabolic adaptations in metabolically active organs including liver , , , , , , fat , , , , , , and heart , , , , both under physiological conditions and in metabolic disorders. In the present review we discuss recent findings on the regulation of the Hippo pathway by metabolism in metabolically active cftr channel and tissues, and its control of metabolic homeostasis and metabolic disorders. The Hippo Pathway – An Overview The Hippo pathway (Figure 1) is a highly conserved master regulator of organ size by controlling several key cellular processes such as proliferation, viability, and differentiation, and its perturbation is associated with multiple pathological disorders such as cancer and diabetes, as well as cardiovascular and neurodegenerative diseases 8, 9, 35, 36. It comprises mammalian sterile 20-like protein kinases 1 and 2 (MST1/2) and large tumor suppressors 1 and 2 (LATS1/2) as core kinases, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) as downstream effectors, and several associated regulatory proteins that function to transmit the extra- and intracellular signals to the core cassette and then to the transcriptional complexes to control cell fate decisions (Box 1). The best-described action of Hippo is to control cell survival and proliferation. Cell culture studies as well as gain- and loss-of-function mouse models of tissue-specific Hippo signaling components have confirmed Hippo pathway-regulated cell survival, cell cycle progression, and tissue regeneration, and have uncovered the functional importance of the Hippo pathway as a powerful regulator of organ size 8, 9, 36. Once activated and ‘ON’, the Hippo pathway – through MST–LATS axis – limits tissue growth and cell proliferation by phosphorylating and inactivating the transcriptional coactivators YAP and TAZ. By contrast, its inactive ‘OFF’ state, with ultimate upregulation and hyperactivation of terminal effectors YAP/TAZ, has been connected with organ development and tissue repair under physiological conditions. Thus, the ‘OFF’ state leads to non-inhibited YAP/TAZ localization in the nucleus and their activation, whereas the ‘ON’ state leads to YAP/TAZ cytoplasmic retention and/or degradation, and YAP/TAZ inhibition by Hippo core components. An extensive ‘OFF’ state can lead to aberrant constitutive activation of YAP/TAZ which is associated with neoplastic growth and multiple types of cancer. Conversely, excessive ‘ON’, in other words hyperactivation of MST or LATS kinases, promotes cell death and is often associated with neurodegenerative and cardiovascular disease as well as with metabolic abnormalities such as diabetes 8, 9, 35, 36. The Hippo pathway responds to a diverse range of extracellular and intracellular inputs including: (i) plasma membrane proteins such as G protein-coupled receptors (GPCRs) or cell–cell junction proteins, (ii) upstream adaptor proteins, which activate core Hippo kinases to specifically phosphorylate and repress YAP/TAZ, (iii) regulatory crosstalk with other signaling pathways such as WNT and mTOR, and (iv) intrinsic and extrinsic mechanical forces and signals such as cell polarity, as well as actin cytoskeleton dynamics 8, 37, 38. For a comprehensive discussion of the basics of Hippo signaling and its molecular mechanisms we refer the reader to recently published reviews 8, 36.