All these recent results show the

All these recent results show the interconnection between the Hippo pathway as a tumor-suppressor on the one hand and its function as regulator of metabolic homeostasis on the other. Disruption of the Hippo pathway leads to cancer growth, which is often associated with pathological disturbances in the metabolic system such as diabetes. As NAFLD, paralleling T2D, reaches epidemic status worldwide [85], novel targets to treat the disease need to be established, and the Hippo pathway, a powerful regulator of cell fate and tissue repair, should be tested, but its additional tumorigenic potential always needs to be kept in mind and carefully monitored.
Hippo Signaling in Adipose Tissue Adipose tissue, an energy-storage depot, is a key metabolic organ in the regulation of systemic energy homeostasis by controlling the production of hormones (adipokines), local and systemic regulation of the lipid cycle of catabolism/anabolism, and metabolic organ-organ cross-communication 86, 87. Adipose tissue includes adipocytes, pre-adipocytes, and immune caudatin australia (i.e., macrophages and leukocytes); all cooperatively balance hormonal and inflammatory signals for proper and tight metabolic homeostasis. Abnormal lipid storage in white adipose tissue (WAT; through hyperplasia and hypertrophy of adipocytes) together with insulin resistance and local inflammation are key events during the development and progression of metabolic diseases such as T2D 86, 87. Cell culture studies as well as in vivo data support a role for the Hippo pathway in the regulation of adipose cell proliferation, differentiation, and adipogenesis 24, 25, 26, 27, 28, 29. Initially, the Hippo transcriptional coactivator TAZ was shown to inhibit adipogenic differentiation by repressing the transcriptional activity the key adipogenic factor peroxisome proliferator-activated receptor γ (PPARγ) [28] (Figure 3B). Later, Hueng et al. [24] showed that the Hippo gene Hpo in Drosophila (homolog of mammalian MST) is involved in fat storage by controlling the number of fat cells. While fat cell-specific overexpression of Hpo reduces fat cell number and whole-body growth, its knockdown promotes fat accumulation and results in weight gain, providing further support for placing Hippo at the nexus of metabolic and growth pathways. Consistent with the negative function of TAZ on adipogenesis, overexpression of Yorkie (Yki, a homolog of mammalian YAP) reversed the proadipogenic function of Hpo in Drosophila[24]. In cultured 3T3-L1 adipocytes, LATS2 was identified as a dual regulator of fat homeostasis, with positive and negative effects on adipocyte differentiation and proliferation, respectively [25]. Whereas activated LATS2 impairs adipocyte proliferation by blocking the G1/S transition and cell cycle progression, it initiates adipocyte differentiation, suggesting Hippo-dependent reciprocal regulation of differentiation/proliferation in adipocytes. Mechanistically, LATS2-induced TAZ phosphorylation and its subsequent inhibition – a canonical Hippo event – promotes PPARγ activity and the expression of proadipogenic genes [25]: this confirms the inhibitory action of TAZ on adipocyte differentiation [28] (Figure 3B). In addition, LATS2-induced inhibition of WNT signaling through cytoplasmic phosphorylated TAZ, which acts as an inhibitor of WNT, contributes to the adipogenic action of LATS2 by repressing proliferation and promoting differentiation [25]. In addition to LATS, Hippo kinases MST1/2 function as positive stimulators of adipogenesis. The expression of MST and its associated protein SAV1 correlates with PPARγ levels and progressively increases during differentiation of pre-adipocytes into adipocytes. Importantly, SAV1 was discovered as direct binding partner of PPARγ, and MST1/2 activity promotes SAV1–PPARγ complex formation, leading to PPARγ protein stabilization and enhancing its adipogenic transcriptional activity [29] (Figure 3B). The group of Guan uncovered further insight into the mechanisms of adipogenesis by identifying cAMP–PKA–RHO signaling as a novel regulator of Hippo–LATS2 to promote adipocyte differentiation [27]. They demonstrated that elevation of intracellular cAMP levels triggered by chemicals and hormonal signals activates PKA, leading to LATS2-induced YAP inhibition in a RHO-dependent manner (Figure 3B). YAP gain- and loss-of-function experiments uncovered an integral role of YAP in PKA-induced adipogenesis, supporting the idea that YAP is an indispensable signal downstream of PKA in regulating adipocyte differentiation [27].