Atrial natriuretic peptide (ANP) is a crucial element of the cardiac endocrine function that promotes natriuresis, diuresis, and vasodilation, thereby protecting normal blood pressure and cardiac function. Corin is a type II transmembrane serine protease that is highly expressed in the heart, where it converts the ANP precursor to mature ANP. Corin deficiency prevents ANP activation and causes hypertension and heart disease. In addition to the heart, corin is expressed in other tissues, including those of the kidney, skin, and uterus, where corin-mediated ANP production and signaling act locally to promote sodium excretion and vascular remodeling. These results indicate that corin and ANP function in many tissues via endocrine and autocrine mechanisms. In heart failure patients, impaired natriuretic peptide processing is a common pathological mechanism that contributes to sodium and body fluid retention. In this review, we discuss most recent findings regarding the role of corin in non-cardiac tissues, including the kidney and skin, in regulating sodium homeostasis and body fluid excretion. Moreover, we describe the molecular mechanisms underlying corin and ANP function in supporting orderly cellular events in uterine spiral artery remodeling. Finally, we assess the potential of corin-based approaches to enhance natriuretic peptide production and activity as a treatment of heart failure.

Atrial natriuretic peptide (ANP) is a key regulator in body fluid balance and cardiovascular biology. In addition to its role in enhancing natriuresis and vasodilation, ANP increases lipolysis and thermogenesis in adipose tissue. Corin is a protease responsible for ANP activation. It remains unknown if corin has a role in regulating adipose tissue function. Here, we examined adipose tissue morphology and function in corin knockout (KO) mice. We observed increased weights and cell sizes in white adipose tissue (WAT), decreased levels of uncoupling protein 1 (Ucp1), a brown adipocyte marker in WAT and brown adipose tissue (BAT), and suppressed thermogenic gene expression in BAT from corin KO mice. At regular room temperature, corin KO and wild-type mice had similar metabolic rates. Upon cold exposure at 4 °C, corin KO mice exhibited impaired thermogenic responses and developed hypothermia. In BAT from corin KO mice, the signaling pathway of p38 mitogen-activated protein kinase, peroxisome proliferator-activated receptor c coactivator 1a, and Ucp1 was impaired. In cell culture, ANP treatment increased Ucp1 expression in BAT-derived adipocytes from corin KO mice. These data indicate that corin mediated-ANP activation is an important hormonal mechanism in regulating adipose tissue function and body temperature upon cold exposure in mice.

Adipose tissue is a crucial organ in energy metabolism and thermoregulation. Adipose tissue phenotype is controlled by various signaling mechanisms under pathophysiological conditions. Type II transmembrane serine proteases (TTSPs) are a group of trypsin-like enzymes anchoring on the cell surface. These proteases act in diverse tissues to regulate physiological processes, such as food digestion, salt-water balance, iron metabolism, epithelial integrity, and auditory nerve development. More recently, several members of the TTSP family, namely, hepsin, matriptase-2, and corin, have been shown to play a role in regulating lipid metabolism, adipose tissue phenotype, and thermogenesis, via direct growth factor activation or indirect hormonal mechanisms. In mice, hepsin deficiency increases adipose browning and protects from high-fat diet-induced hyperglycemia, hyperlipidemia, and obesity. Similarly, matriptase-2 deficiency increases fat lipolysis and reduces obesity and hepatic steatosis in high-fat diet-fed mice. In contrast, corin deficiency increases white adipose weights and cell sizes, suppresses adipocyte browning and thermogenic responses, and causes cold intolerance in mice. These findings highlight an important role of TTSPs in modifying cellular phenotype and function in adipose tissue. In this review, we provide a brief description about TTSPs and discuss recent findings regarding the role of hepsin, matriptase-2, and corin in regulating adipose tissue phenotype, energy metabolism, and thermogenic responses.

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