*7.1. Obesity*

Obesity, characterized by excessive accumulation of body fats, is a representative of the modifiable risk factors for cardiovascular diseases including hypertension and atherosclerosis [100]. Based on the fortuitous finding that TCTP-TG mice with C57BL/6N background have the phenotypes of relatively lighter body weight than control mice, our group investigated the impact of TCTP on metabolic tissues and systemic energy metabolism [47]. We confirmed that TCTP-TG mice of C57BL/6N strain under normal chaw diet (NCD) showed significantly lower body weight compared to wild-type mice (WT) as early as six weeks after birth despite their comparable amount of food intake [47]. TCTP-TG showed an increase in muscle weight and reduction in fat mass due to inhibition of the hypertrophy of adipocytes in epididymal white adipose tissue (WAT). In addition, TCTP-TG exhibited improvement in hepatic lipid accumulation, plasma lipid profiles, and glucose tolerance as well as overall energy expenditures [47]. When we compared the metabolic homeostasis between TCTP-TG and WT under NCD and high-fat diet (HFD) conditions, TCTP-TG indicated improved metabolic homeostasis under both conditions, with the enhanced glucose tolerance and insulin sensitivity [47].

Upon cold exposure that triggers thermogenesis by the sympathetic nerve system (SNS) activation in the brown adipose tissue (BAT), TCTP-TG showed improved adaptive thermogenesis [47]. TCTP overexpression attenuated systemic metabolic imbalance by upregulating the uncoupling protein 1 (UCP1)-mediated thermogenesis in the BAT, serving as a modulator in the process of energy expenditure [47]. Affluent mitochondria contained in the BAT, where mitochondrial carrier protein, UCP1, mediates thermogenesis by sympathetic stimuli and produces heat by consuming triglycerides [101]. BAT activation is reported to reduce hypercholesterolemia and to exert protective roles from atherogenesis [102]. More importantly, TCTP-TG exhibited resistance to HFD-induced obesity and metabolic disorders [47]. The increase in energy expenditure and thermogenesis of BAT under HFD in TCTP-TG underscores the critical roles of TCTP in metabolic homeostasis through energy expenditure [47]. Therefore, TCTP can be viewed as a rational target for the energy expenditure-related conditions such as obesity and metabolic disorders [47].

#### *7.2. Heart Failure*

A recent publication by Cai et al. addressed TCTP's role in cardiomyocyte survival based on the observation that an animal model overexpressing cardiomyocyte-specific TCTP-TG showed a protective role in heart failure [49]. Cardiomyocyte-specific TCTP overexpression drastically reduced the susceptibility to doxorubicin (DOX)-induced cardiac dysfunction in mice [49]. It also inhibited the induction of Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (Bnip3), a molecule that mediates the TCTP-loss-induced cardiomyocyte death [49]. In mice with cardiomyocyte-specific TCTP overexpression, treatment with dihydroartemisinin, a pharmacological TCTP inhibitor, did not induce heart failure and cardiomyocyte death, both of which were induced in control mice [49]. Altogether, these observations show that TCTP is essential for cardiomyocyte survival and can be suggested as a therapeutic target that ameliorates DOX-induced heart failure [49].

In addition, studies in an animal model that lacks TCTP in their heart confirm the protective role of TCTP in heart failure [50]. Mice devoid of TCTP expression in the heart showed premature death by 9 weeks of age because of extensive apoptotic cardiomyocytes and severe heart failure [50]. Heart-specific TCTP KO mice showed upregulation of p53 target genes in their hearts and heart-targeted deletion of p53 in those mice prolonged survival of mice from 9 to 18 weeks by preventing apoptosis of cardiomyocytes. Therefore, this group concluded that inappropriate expression of TCTP is related to the pathophysiology of heart failure [50].

#### **8. Conclusions**

New perspectives on the pathophysiological roles of TCTP as a multifunctional protein as well as a cytosolic sodium pump inhibitor and as a player in the development of systemic and arterial hypertension, cardiac hypertrophy, cataracts, diabetes, and related disorders via inhibition of the sodium pump in VSMC, lens epithelial, or other relevant cells have emerged from the studies of genetically engineered animal models. Additionally, TCTP accelerates the pathogenesis and severity of atherosclerosis by the mechanisms involving its anti-apoptotic activity on macrophages in atherosclerotic lesions. Conversely, modalities that modulate TCTP could be a promising strategy in the therapeutics for systemic hypertension, hypertension-induced atherosclerosis, and cataracts, all of which are associated with Na,K-ATPase suppression.

Intriguingly, TCTP also showed beneficial effects on heart failure and obesity by protecting the cells from apoptosis and enhancing the metabolic expenditure, respectively, in animal models. Because TCTP has a plethora of physiological functions and is essential for the survival and growth of cells and organisms, a certain extent of TCTP expression in vivo seems indispensable for maintaining normal physiology. However, not only excessive but also deficient expression of TCTP is related to the pathophysiology in specific conditions, as shown in the phenotypes of TCTP-TG and TCTP+/<sup>−</sup> mice. Further studies regarding hitherto unknown potential mechanisms and roles of TCTP in terms of various cellular functions might delineate its pathophysiological network in the cardiovascular conditions. In this perspective, possible implications of TCTP in the cellular senescence and its contributory mechanism in the arterial hypertension and related disorders can be one of the future studies based on the causative roles of senescence in the majority of cardiovascular diseases [103,104].

It is challenging, at present, to describe the complicated networking between protective and causative roles of TCTP in a unified figure, and disease-specific mechanisms, and regulations affecting the expression and activity of TCTP need to be delineated for future investigations. Clearly, studies in disease-specific animal models and human cases may help us understand how TCTP exerts manifold functions in a certain disease and pave the way for TCTP-targeting therapeutics.

**Author Contributions:** Conceptualization, J.M. and K.L.; writing—original draft preparation, J.M.; writing—review & editing, K.L.; supervision, K.L.; project administration, K.L.; funding acquisition, K.L. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was supported by the Bio and Medical Technology Development Program (2020M3E5E2036808) and (2021R1A2C2003629) by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT).

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.
