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Neuropeptide FF (NPFF) is an endogenous octapeptide that was originally isolated from the bovine brain. It belongs to the RFamide family of peptides that has a wide range of physiological functions and pathophysiological effects. NPFF and its receptors, NPFFR1 and NPFFR2, abundantly expressed in rodent and human brains, participate in cardiovascular regulation. However, the expressions of NPFF and its receptors are not restricted within the central nervous system but are also found in peripheral organs, including the kidneys. Both NPFFR1 and NPFFR2 mainly couple to Gαi/o, which inhibits cyclic adenosine monophosphate (cAMP) production. NPFF also weakly binds to other RFamide receptors and the Mas receptor. Relevant published articles were searched in PubMed, Google Scholar, Web of Science, and Scopus. Herein, we review evidence for the role of NPFF in the regulation of blood pressure, in the central nervous system, particularly within the hypothalamic paraventricular nucleus and the brainstem, and the kidneys. NPFF is a potential target in the treatment of hypertension.

Acute renal depletion of sorting nexin 1 (SNX1) in mice results in blunted natriuretic response and hypertension due to impaired dopamine D 5 receptor (D 5 R) activity. We elucidated the molecular mechanisms for these phenotypes in Snx1 -/- mice. These mice had increased renal expressions of angiotensin II type 1 receptor (AT 1 R), NADPH oxidase (NOX) subunits, D 5 R, and NaCl cotransporter. Basal reactive oxygen species (ROS), NOX activity, and blood pressure (BP) were also higher in Snx1 -/- mice, which were normalized by apocynin, a drug that prevents NOX assembly. Renal proximal tubule (RPT) cells from hypertensive (HT) Euro-American males had deficient SNX1 activity, impaired D 5 R endocytosis, and increased ROS compared with cells from normotensive (NT) Euro-American males. siRNA-mediated depletion of SNX1 in RPT cells from NT subjects led to a blunting of D 5 R agonist-induced increase in cAMP production and decrease in Na + transport, effects that were normalized by over-expression of SNX1. Among HT African-Americans, three of the 12 single nucleotide polymorphisms interrogated for the SNX1 gene were associated with a decrease in systolic BP in response to hydrochlorothiazide (HCTZ). The results illustrate a new paradigm for the development of hypertension and imply that the trafficking protein SNX1 may be a crucial determinant for hypertension and response to antihypertensive therapy., (© 2020 Federation of American Societies for Experimental Biology.)

Objective: In mouse models, deficiency of TTC39B (T39) decreases hepatic lipogenic gene expression and protects against diet-induced steatohepatitis. While assessing the therapeutic potential of antisense oligonucleotides (ASOs) targeting T39, we discovered an unexpected weight loss phenotype. The objective of this study was to determine the mechanism of the resistance to diet-induced obesity., Methods: To assess therapeutic potential, we used antisense oligonucleotides (ASO) to knock down T39 expression in a Western or high-fat, high-cholesterol, high-sucrose-diet-fed Ldlr -/- or wild-type mice., Results: T39 ASO treatment led to decreased hepatic lipogenic gene expression and decreased hepatic triglycerides. Unexpectedly, T39 ASO treatment protected against diet-induced obesity. The reduced weight gain was seen with two different ASOs that decreased T39 mRNA in adipose tissue macrophages (ATMs), but not with a liver-targeted GalNac-ASO. Mice treated with the T39 ASO displayed increased browning of gonadal white adipose tissue (gWAT) and evidence of increased lipolysis. However, T39 knockout mice displayed a similar weight loss response when treated with T39 ASO, indicating an off-target effect. RNA-seq analysis of gWAT showed a widespread increase in type I interferon (IFN)-responsive genes, and knockout of the IFN receptor abolished the weight loss phenotype induced by the T39 ASO. Some human T39 ASOs and ASOs with different modifications targeting LDLR also induced a type I IFN response in THP1 macrophages., Conclusion: Our data suggest that extrahepatic targeting of T39 by ASOs in ATMs produced an off-target type 1 IFN response, leading to activation of lipolysis, browning of WAT, and weight loss. While our findings suggest that ASOs may induce off-target type 1 IFN response more commonly than previously thought, they also suggest that therapeutic induction of type 1 IFN selectively in ATMs could potentially represent a novel approach to the treatment of obesity., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Expressed in the small intestine, retinol-binding protein 2 (RBP2) facilitates dietary retinoid absorption. Rbp2 -deficient ( Rbp2 -/- ) mice fed a chow diet exhibit by 6-7 months-of-age higher body weights, impaired glucose metabolism, and greater hepatic triglyceride levels compared to controls. These phenotypes are also observed when young Rbp2 -/- mice are fed a high fat diet. Retinoids do not account for the phenotypes. Rather, RBP2 is a previously unidentified monoacylglycerol (MAG)-binding protein, interacting with the endocannabinoid 2-arachidonoylglycerol (2-AG) and other MAGs with affinities comparable to retinol. X-ray crystallographic studies show that MAGs bind in the retinol binding pocket. When challenged with an oil gavage, Rbp2 -/- mice show elevated mucosal levels of 2-MAGs. This is accompanied by significantly elevated blood levels of the gut hormone GIP (glucose-dependent insulinotropic polypeptide). Thus, RBP2, in addition to facilitating dietary retinoid absorption, modulates MAG metabolism and likely signaling, playing a heretofore unknown role in systemic energy balance., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

All-trans-retinoic acid (ATRA) has been well described as a positive regulator for early stage of adipocyte differentiation and lipid metabolism and also linked to an in vivo fat-lowering effect in mice. However, not all studies support this association. Our objective was to characterize the action of ATRA in mature adipocytes of mice by ablating RAR signaling through overexpression of a well-characterized dominant negative RARα mutant (RARdn) form specifically in adipocytes. Altered RAR signaling in adipocytes resulted in a significant decrease in ATRA levels in visceral and brown adipose tissues as well as liver tissue. This was linked to significant impairments in glucose clearance and elevated hepatic lipid accumulation for chow diet fed mice, indicating the development of metabolic disease, including hepatic steatosis. In addition, we found that adipose RARdn expression in mice fed a chow diet decreased thermogenesis. We conclude that altered RAR signaling and ATRA levels in adipocytes impacts glucose and lipid metabolism in mice., (Copyright © 2019 Elsevier Inc. All rights reserved.)

There is widespread evidence that increasing functional mass of brown adipose tissue (BAT) via browning of white adipose tissue (WAT) could potentially counter obesity and diabetes. However, most current approaches focus on administration of pharmacological compounds which expose patients to highly undesirable side effects. Here, we describe a simple and direct tissue-grafting approach to increase BAT mass through ex vivo browning of subcutaneous WAT, followed by re-implantation into the host; this cell-therapy approach could potentially act synergistically with existing pharmacological approaches. With this process, entitled "exBAT", we identified conditions, in both mouse and human tissue, that convert whole fragments of WAT to BAT via a single step and without unwanted off-target pharmacological effects. We show that ex vivo, exBAT exhibited UCP1 immunostaining, lipid droplet formation, and mitochondrial metabolic activity consistent with native BAT. In mice, exBAT exhibited a highly durable phenotype for at least 8 weeks. Overall, these results enable a simple and scalable tissue-grafting strategy, rather than pharmacological approaches, for increasing endogenous BAT and studying its effect on host weight and metabolism.

The homeostatic control of blood pressure hinges upon the delicate balance between prohypertensinogenic and antihypertensinogenic systems. D₁-like dopamine receptors [dopamine D₁ and D₅ receptors (D₁Rs and D₅Rs, respectively)] and the α₁A-adrenergic receptor (α₁A-AR) are expressed in the renal proximal tubule and engender opposing effects on Na(+) transport, i.e., natriuresis (via D₁Rs and D5Rs) or antinatriuresis (via α₁A-ARs). We tested the hypothesis that the D₁R/D₅R regulates the α₁A-AR. D₁-like dopamine receptors coimmunoprecipitated, colocalized, and cofractionated with α₁A-ARs in lipid rafts in immortalized human renal proximal tubule cells. Long-term treatment with the D₁R/D₅R agonist fenoldopam resulted in decreased D₁R and D₅R expression but increased α₁A-AR abundance in the plasma membrane. Short-term fenoldopam treatment stimulated the translocation of Na(+)-K(+)-ATPase from the plasma membrane to the cytosol that was partially reversed by an α₁A-AR agonist, which by itself induced Na(+)-K(+)-ATPase translocation from the cytosol to the plasma membrane. The α₁A-AR-specific agonist A610603 also minimized the ability of fenoldopam to inhibit Na(+)-K(+)-ATPase activity. To determine the interaction among D₁Rs, D₅Rs, and α₁A-ARs in vivo, we used phenylephrine and A610603 to decrease Na(+) excretion in several D1-like dopamine receptor knockout mouse strains. Phenylephrine and A61603 treatment resulted in a partial reduction of urinary Na(+) excretion in wild-type mice and its abolition in D1R knockout, D₅R knockout, and D₁R-D₅R double-knockout mice. Our results demonstrate the ability of the D₁-like dopamine receptors to regulate the expression and activity of α₁A-AR. Elucidating the intricacies of the interaction among these receptors is crucial for a better understanding of the crosstalk between anti- and pro-hypertensive systems.

The present study was performed to detect the presence of gap junction protein connexin 43 (Cx43) and describe the changes in its expression during ovarian follicular atresia in the swamp buffalo in comparison with cattle. Ovaries of Philippine swamp buffaloes (Bubalus bubalis; SB) and Holstein-Friesian cows (Bos taurus; HF) were collected from slaughterhouses, fixed in 10% formalin in PBS and embedded in paraffin. Sections of healthy follicles and at various follicular stages of atresia were immunostained with anti-Cx43 antibody. Cx43 appeared as punctate staining between granulosa cells (healthy to advanced atretic follicles), indicating assembled gap junctions, but was absent in the theca interna. In SB as well as in HF, granulosa cells showed a dense, moderate, and sparse immunoreactivity to Cx43 in healthy, early atretic, and advanced atretic follicles, respectively. Cumulus cells (in the advanced atretic follicle) surrounding oocytes and adjacent granulosa layers retain the Cx43 protein, although there was only a sparse expression of Cx43 observed in the granulosa layers distant from oocytes in the same follicles. The results indicate that gap junction protein Cx43 decreases in association with atresia and supports the concept that a loss of gap junctional communication plays a coordinating role in the process of atresia. Furthermore, the schema of Cx43 immunoreactivity in SB granulosa cells is similar to that of HF.

The aim of this study was to investigate the distribution pattern of von Willebrand factor (vWF) and vascular endothelial growth factor (VEGF) in the healthy antral and atretic follicles of Philippine swamp buffaloes (SB) in comparison with Holstein-Friesian cows (HF). Paraffin sections of healthy follicles and atretic follicles at various stages were immunostained with vWF antibody and VEGF antibody. The density of vWF-positive capillary vessels in the theca interna significantly increased as atresia progressed in SB, whereas the density significantly decreased in late atretic follicles compared with advanced ones in HF. On the other hand, the area of vWF-positive capillary vessels in the theca interna significantly increased as atresia progressed in both SB and HF. Immunoreactions of VEGF in the granulosa cells (in all follicle types) were observed in both SB and HF. In the granulosa layer, a reduction in the VEGF immunoreaction was noted as follicles progressed from healthy to advanced atretic follicles in both animals. Granulosa cells (in both SB and HF) showed a higher immunopositive staining than theca cells. In the theca interna, VEGF immunostaining diminished as follicles progressed to the late atretic follicles in both animals. These results indicate that during atresia, changes of vWF expression are the opposite of VEGF expression in SB. Both vWF and VEGF are suggested to be associated with follicular atresia in SB.

This study aimed to describe the changes in the thecal vasculature during ovarian follicular atresia in the swamp buffalo. Ovaries of Philippine swamp buffalo (Bubalus bubalis; SB), crossbred (SB x Murrah buffalo; CB) and Holstein-Friesian cow (Bos taurus; HF) were collected from slaughterhouses, fixed in 10% formalin in PBS and embedded in paraffin. Sections of healthy follicle and various follicular stages of atresia were stained with Bandeiraea simplicifolia-I lectin (BSL-I) to visualize the endothelial cells of blood vessels. In the theca interna, healthy follicles in SB had a significantly lower number of capillary vessels than other breeds and other atretic stages of follicle. From healthy to early atretic follicle, theca interna in all breeds showed a significant decrease in the area of capillary vessel. Capillary vessel area significantly increased (but was smaller than in healthy follicle) in the middle stage of atresia and declined again in the late atretic follicle (greater than in early atresia but smaller than in healthy follicle) in SB only. No significant change in the capillary vessel area of theca interna was noted in both CB and HF from early to late atretic follicles. There was no significant difference in the capillary vessel number and area of theca externa among the different breeds and atretic stages of follicle. These results suggest that there are dynamic changes occurring in the thecal vasculature of SB but not CB during follicular atresia which differs among cattle.