Type II Transmembrane Serine Proteases as Modulators in Adipose Tissue Phenotype and Function

Abstract

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.

Precision nutrition to reset virus-induced human metabolic reprogramming and dysregulation (HMRD) in long-COVID

“…Viral membrane fusion priming enzyme furin , is known for intracellular proteolytic processing of precursor polypeptides, which is an essential step in the maturation of many proteins such as plasma proteins, hormones, neuropeptides, and growth factors 331 . Viral membrane fusion priming enzyme TMPRSS2 plays a key role in digestion, salt-water balance, iron metabolism, tissue remodeling, blood coagulation, auditory nerve development, and fertility 366 . Viral endocytosis-mediator CTSL is involved in functional development of immune system, skeletal physiology including bone collagen degradation/resorption and thyroid hormone release 384 , 385 .…”

“…Human TMPRSS2 mRNA is expressed in many tissues, including prostate, breast, bile duct, kidney, colon, small intestine, pancreas, ovary, salivary gland, stomach, and lungs 365 . TMPRSS2 plays a vital role in several biological functions such as digestion, salt-water balance, iron metabolism, tissue remodeling, blood coagulation, auditory nerve development, and fertility 366 . It is also required for many pathobiological pathways that involve inflammatory responses, tumor cell invasion, apoptosis, and pain 367 .…”

“…As a membrane-anchored enzyme of the host cellular machinery, TMPRSS2 activates precursor molecules in the pericellular milieu to establish metabolic homeostasis 362 . Viral hijacking of this protease could dysregulate lipid metabolism, adipose tissue phenotype, and thermogenesis via direct growth factor activation or indirect hormonal mechanisms 366 . TMPRSS2 expression is high in human prostate gland and this enzyme regulates sperm function in the seminal prostasome 357 .…”

Chenodeoxycholic Acid-Loaded Nanoparticles Are Sufficient to Decrease Adipocyte Size by Inducing Mitochondrial Function

“…44,46,47 Proteases such as serine proteases, cysteine proteases, and metalloproteinases are expressed in adipose tissue and regulate its metabolic function and adipogenesis. 48,49 Therefore, we conjecture that the observed release profile from the CDCA-GNPs in the proteolytic enzyme-free media is mostly through diffusion, and the CDCA-GNPs deposited in adipose tissues will have stable zero-order release kinetics with a minimal burst release in vivo prior to cellular internalization due to the stability of the GNPs in the absence of gelatindegrading proteases. Once GNPs are taken up by adipocytes, intracellular proteases may facilitate the release of CDCA from biodegradable GNPs.…”

“…Roughly 65% of total CDCA was released within 3 days, followed by zero-order release until day 15 to reach complete release, demonstrating a reliable release kinetics of our GNPs for long-term BA delivery applications (Figure B). The drug is released from GNPs mainly through diffusion and protease-triggered degradation of the gelatin matrix. ,, Proteases such as serine proteases, cysteine proteases, and metalloproteinases are expressed in adipose tissue and regulate its metabolic function and adipogenesis. , Therefore, we conjecture that the observed release profile from the CDCA-GNPs in the proteolytic enzyme-free media is mostly through diffusion, and the CDCA-GNPs deposited in adipose tissues will have stable zero-order release kinetics with a minimal burst release in vivo prior to cellular internalization due to the stability of the GNPs in the absence of gelatin-degrading proteases. Once GNPs are taken up by adipocytes, intracellular proteases may facilitate the release of CDCA from biodegradable GNPs.…”