Grobe, J. L. | bioRxiv Science

bioRxiv2026

Adipocyte Expression of O-Glycoprotein Procollagen C-Endopeptidase Enhancer Protein 2 (PCPE2): Mechanisms Linking Fibrosis and Beiging of White Adipose Tissue

BackgroundProcollagen C-endopeptidase enhancer protein 2 (Pcpe2) has been primarily investigated in collagen processing during wound healing and is assumed to function similarly to Pcpe1 in the extracellular matrix (ECM). Our studies suggest that Pcpe2 has unique structural and functional features not shared with Pcpe1. MethodsTo study the role of Pcpe2 in adipose tissue remodeling, we created adipose tissue-specific knockout of Pcpe2 (TgAd+Pcpe2KO) and adipose tissue-specific Pcpe2 overexpressing (TgAd+Pcpe2Ox) mice and performed in vivo and ex vivo experiments. ResultsWe show that TgAd+Pcpe2KO mice are resistant to WD-induced obesity and exhibit reductions in body and fat pad mass. Promethion cage studies showed no significant differences in lean mass or food intake, yet WD-fed TgAd+Pcpe2KO mice exhibited significantly higher energy expenditure than negative Cre littermate controls. WD-fed TgAd+Pcpe2KO mice also showed reduced plasma glucose and lipoprotein lipid concentrations compared to controls. While markers of adipose tissue inflammation were reduced in WD-fed TgAd+Pcpe2KO mice. Examination of mature adipocytes from white adipose tissue showed that WD consumption greatly stimulated Pcpe2 expression, while no change in Pcpe2 expression in the stromal vascular cells was noted. However, in VAT precursor cells (PCs), the CD140b+ population showed a shift from fibroadipogenic precursors towards adipocyte PCs in TgAd+Pcpe2KO mice. This shift in PCs may account for the attenuation of local inflammation and fibrosis in the absence of Pcpe2. Ex vivo differentiation of adipose PCs showed that loss of Pcpe2 enhanced adipocyte differentiation, reducing TGF{beta}-like signaling via pSmad2/3, and increasing mitochondrial function. Furthermore, unlike Pcpe1, Pcpe2 contains a mucin-like linker domain with nine sites of O-linked glycosylation which may regulate receptor signaling at the plasma membrane. ConclusionsOur results show the ECM O-glycoprotein Pcpe2 is a robust marker of unhealthy adipose tissue expansion in humans and mice and contributes to inflammation and fibrosis associated with WD-induced obesity.

cell biology↗

bioRxiv2021

Studies of Salt and Stress Sensitivity on Arterial Pressure in Renin-b Deficient Mice

Excessive sodium intake is known to increase the risk for hypertension, heart disease, and stroke. Individuals who are more susceptible to the effects of high salt are at higher risk for cardiovascular diseases even independent of their blood pressure status. Local activation of the renin-angiotensin system (RAS) in the brain, among other mechanisms, has been hypothesized to play a key role in contributing to salt balance. We have previously shown that deletion of the alternative renin isoform termed renin-b disinhibits the classical renin-a encoding preprorenin in the brain resulting in elevated brain RAS activity. Thus, we hypothesized that renin-b deficiency results in higher susceptibility to salt-induced elevation in blood pressure. Telemetry implanted Ren-bNull and wildtype littermate mice were first offered a low salt diet for a week and subsequently a high salt diet for another week. A high salt diet induced a mild blood pressure elevation in both Ren-bNull and wildtype mice, but mice lacking renin-b did not exhibit an exaggerated pressor response. When renin-b deficient mice were exposed to a high salt diet for a longer duration (4 weeks), was a trend for increased myocardial enlargement in Ren-bNull mice when compared with control mice. Multiple studies have also demonstrated the association of chronic and acute environmental stress with hypertension. Activation of the RAS in the rostral ventrolateral medulla and the hypothalamus is required for stress-induced hypertension. Thus, we next questioned whether the lack of renin-b would result in exacerbated response to an acute restraint-stress. Wildtype and Ren-bNull mice equally exhibited elevated blood pressure in response to restraint-stress, which was similar in mice fed either a low or high salt diet. These studies highlight a complex mechanism that masks/unmasks roles for renin-b in cardiovascular physiology.

physiology↗