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Global Translational Medicine Mineralocorticoid receptor in CMD

leads to abnormal responses to physiological signals and the heterogeneity of adipose tissue. The function of MR
contributes to the progression of CMD, along with other in other cell types should be taken into consideration in
pathological consequences. In the last decade, studies have future work.
revealed that MR plays an important role in adipose tissue,
where MR is involved in regulating the pathophysiological 5.3. Function of MR in brown adipocyte
process of adipocytes, including differentiation, autophagy, Several in vitro studies have shown that MR activation
and adipokine secretion [106] . The regulatory role of MR in reduces the expression of uncoupling protein 1 (UCP-1),
white and brown adipocytes is discussed below. which is a thermogenic marker, during brown adipocyte
differentiation [124,125] . Finerenone, a nonsteroidal MR
5.2. Function of the MR in white adipocyte antagonist, has been shown to improve the metabolic
Several studies have demonstrated that MR has an parameters of high-fat diet-induced obese mice in vivo
essential role in regulating white adipocyte differentiation through brown adipose tissue (BAT) activation, without
and adipogenesis in vitro [107-109] . However, Lee et al. have affecting WAT expansion [126,127] . Notably, a recent clinical
provided a contrary perspective that instead of MR, GR study has revealed that spironolactone increases human
plays a dominant role in cortisol-mediated adipogenesis BAT activity in response to cold stimuli and food intake [128] .
and adipokine production in human adipocytes [110] . Given These studies suggest that brown adipocyte MR plays an
the different conditions used in these studies, the individual important role in the control of energy expenditure in
and cooperative roles of MR and GR in regulating adipocyte metabolic diseases. Further investigations are needed
differentiation require further investigation. to determine the exact role of MR in brown adipocyte
function and CMD.
MR expression is increased in the adipose tissue of
obese mouse model and obese patients [111,112] . Notably, 6. Role of osteoblast MR in cardiac
the metabolic benefits of MR antagonists have been remodeling
widely demonstrated by several animal studies [40,111,113,114] .
MR blockade reverses obesity-induced white adipocyte Osteoblasts have endocrine functions and play important
dysfunction and insulin resistance as well as promotes roles in homeostatic regulation of the internal environment
the browning of white adipose tissue (WAT). Moreover, of the body [129,130] . Osteoblast MR deletion diminishes
MR activation is involved in obesity-induced vascular atrial fibrosis in mutant transforming growth factor beta 1
dysfunction. On the contrary, MR blockade by potassium (TGF-β1) transgenic mice by suppressing osteocalcin
canrenoate improves adipose tissue senescence and (OCN) expression [131] . In cultured atrial fibroblasts, OCN
vascular dysfunction in obesity [115] . Besides, adipocyte MR binds to G protein-coupled receptor family C group 6
overexpression leads to impaired vascular contractility member A (GPRC6A) and promotes the phosphorylation
in non-obese mice [116] . Interestingly, a recent human of protein kinase A (PKA) and cAMP-response
study has shown that eplerenone inhibits interstitial element binding protein (CREB), thereby increasing
fibrosis in subcutaneous adipose tissue in type 2 diabetes fibroblast proliferation and migration [131] . Osteoblast
patients [117] . Another recent study has demonstrated that MR deficiency has shown to improve cardiac function
spironolactone ameliorates diet-induced hepatic steatosis and inhibit adverse cardiac remodeling in a mouse MI
and insulin resistance by improving WAT browning and model [132] . Mechanistically, calvaria ribonucleic acid
inhibiting hepatic mitochondria dysfunction, oxidative (RNA) sequencing data have revealed that MR knockout
stress, and inflammation [118] . However, the exact role of decreases the expression of OCN, which works through
white adipocyte MR in obesity and its associated metabolic GPRC6A to increase the phosphorylation level of ERK in
disorders remains uncertain. Several studies using genetic cultured macrophages, thereby promoting macrophage
adipocyte-specific MR overexpression or knockout mice proliferation and pro-inflammatory phenotypic
have revealed a deteriorative effect of adipocyte MR on the differentiation [132] . Consistently, MR antagonists have been
regulation of obesity-related metabolic disorders [112,119,120] . shown to inhibit the expression and secretion of OCN in
However, two other studies have shown that the depletion post-MI mice and HF patients, which further suggests
of MR in mature adipocytes exerts minor to modest the existence of MR/OCN axis-mediated communication
improvements on obesity-associated glucose intolerance, between osteoblast and the heart in pathological cardiac
insulin resistance, and hepatic steatosis [121,122] . In addition, remodeling [132] .
another study has observed a relative resistance to diet- 7. MR antagonists and clinical applications
induced obesity in transgenic mice overexpressing human
MR [123] . The discrepancy between adipocyte MR genetic Clinical trials have demonstrated that MR antagonists
manipulation and MR antagonists could be attributed to (MRAs) have beneficial effects in treating CVD .
[7]

Volume 2 Issue 1 (2023) 9 https://doi.org/10.36922/gtm.v2i1.229