ATVB Recent Highlights: Emerging Roles for Adipose Tissue in Cardiovascular Disease

Cardiovascular disease (CVD), diabetes and insulin resistance, and other obesity-related disorders remain a heavy disease burden in the United States and throughout the world.¹ These disorders are interconnected, and adipose tissue is increasingly understood to be an important nexus of these related diseases. Adipose tissue itself is comprised of multiple cell types, including adipocytes, monocytes/macrophages, pericytes, endothelial cells, and various stem cells, and is thus a highly dynamic tissue with many functions. Additionally, adipose can alter the function of other tissues (liver, brain, heart, skeletal muscle, vascular endothelium) from afar via the secretion of adipokines and bioactive molecules, thus making it a critical endocrine regulator of whole body metabolism. Given these functions, healthy adipose is important for metabolic homeostasis, while dysfunctional adipose is a contributing factor to metabolic disease pathogenesis. In this Recent Highlights article, we discuss recent publications from Arteriosclerosis, Thrombosis, and Vascular Biology and other journals that investigate this highly complex tissue and its various emerging roles in cardiovascular disease pathophysiology.

Regulation of Serum Lipids by Adipose Tissue

Adipose tissue is distinguished from other tissues by the presence of adipocytes, cells which contain either a single large lipid droplet (white adipose tissue) or multiple lipid droplets (brown adipose tissue). Not surprisingly, the most widely known and recognized function of adipose is its role in the storage and release of lipid species, particularly fatty acids (FA). The lipid droplet is composed of lipid esters that are either synthesized by the adipocytes or processed from circulating lipids.² Adipocytes release FAs into the bloodstream via lipolysis of lipids in the lipid droplet by consecutive hydrolysis by adipose triglyceride lipase (ATGL), hormone sensitive lipase (HSL), and monoglyceride lipase (MGL) in response to energy demand.³ Thus, lipolysis by HSL and ATGL is under homeostatic control, and is known to be regulated by several signals, most notably natriuretic peptides (activating), insulin (inhibiting), and catecholamines (activating or inhibiting depending on context).⁴ In a recent report, Rydén et. al. sought to determine the extent of the contribution of adipose lipolysis to serum lipid levels by measuring basal lipolysis and responses to hormonal regulators of lipolysis in over 1000 human subcutaneous adipose samples.⁵ In this study, basal lipolysis and resistance to antilipolytic insulin signaling were found to correlate with low plasma HDL-cholesterol (HDL-C) and high triglycerides (TG). Furthermore, 14% of variations in HDL-C and TG levels could be explained by basal lipolysis and responsiveness to insulin, supporting an important role for adipocyte lipolysis in regulating serum lipid levels.

Adipocytes also regulate serum lipids via uptake of TGs from circulating lipoprotein particles, such as chylomicrons and very-low-density lipoprotein (VLDL) particles.⁶ Notably, adipocytes are a major source of lipoprotein lipase (LPL), the main enzyme that hydrolyzes the TG in lipoproteins to FA in the periphery, and dysfunction in the TG/LPL axis can have numerous adverse effects.⁷ After hydrolysis, FAs are available for uptake by adipocytes, at which point they are reesterified and stored as TGs in the lipid droplet.⁸ Healthy adipose theoretically stores lipids in high-energy settings, such as during the postprandial state, and releases FAs to provide energy for tissues in low-energy settings (i.e. fasting). However, adipose tissue becomes dysfunctional in obesity-related diseases, with hypertrophied adipocytes and increased basal lipolysis.⁹ Thus, understanding the factors that regulate lipid accumulation in adipocytes will aid in understanding the mechanisms of obesity and related diseases.

In a recent study from Gao et. al.,¹⁰ the authors found a positive association between serum sodium levels and serum lipid parameters (total cholesterol, LDL-cholesterol (LDL-C), total cholesterol to HDL-cholesterol ratio) using data from subjects in the Atherosclerosis Risk in Communities (ARIC) study with sodium levels in the normal range of 135–145 mmol/L. This finding suggests that sodium levels may be a regulator of lipid metabolism. In support of this, the authors found that 3T3-L1 adipocytes had increased lipid droplet accumulation when differentiated in hypertonic culture medium (higher concentrations of sodium or sorbital). Furthermore, the group identified a positive association of body-mass-index and waist-to-hip ratio with serum sodium in subjects from the ARIC study. Thus, the authors proposed hypertonicity as a novel regulator of lipid accumulation in adipocytes, and further hypothesized that the effect may be mediated by the transcription factor NFAT5, the only mammalian transcription factor known to be induced by hypertonicity. While NFAT5 is mostly known for its role in adaptation to osmotic stress,¹¹ it has been implicated in atherogenesis as ApoE−/− mice haplosufficient for Nfat5 had decreased atherosclerotic lesion development.¹² Interestingly, another group reported that high salt intake resulted in decreased fat mass in mice, and that high sodium treatment resulted in decreased lipid accumulation in 3T3-L1 cells.¹³ Perhaps a major difference between these two studies is Gao et. al.’s focus on long-term effects of variances in normal levels of sodium levels while the second report focused on a more extreme model of high sodium levels. Further studies would be needed to understand the mechanism of hypertonicity on adipocyte lipid accumulation.

Recent studies have identified that adipocytes can directly affect HDL-C levels via efflux of cholesterol through the ATP-binding cassette transporter A1 (ABCA1) transporter.¹⁴ Cuffe et. al.¹⁵ generated adipocyte-specific Abca1 knock-out mice and observed that these mice have decreased plasma total cholesterol and HDL-C levels; additionally, these mice had 3-fold increased adipose cholesterol content, especially in the plasma membranes of adipocytes, highlighting the importance of Abca1 in adipocyte cholesterol flux. Interestingly, the mice exhibited attenuated diet-induced obesity, as well as decreased adipocyte hypertrophy, TG accumulation, and de novo lipogenesis. This is surprising, given the general negative association between HDL-C levels and obesity,¹⁶ as well as previous observations that increased adipocyte cholesterol associates with adipocyte hypertrophy and increased TG accumulation.¹⁷ As pointed out by Cuffe et. al. and editorialized by la Rose et. al., this study points out an important role specifically for membrane cholesterol in adipocyte lipid regulation through the SREBP pathways.¹⁸ Additionally, the role of the ABCA1 transporter is likely cell dependent, and disease states (i.e. Tangier disease) resulting from ABCA1 deficiency are a combination of effects from lack of cholesterol efflux from both macrophages and adipocytes. Given the cellular heterogeneity of adipose tissue, the use of cell-specific models, such as those used in this study, is critical for understanding mechanisms of adipose tissue regulation of lipids.

While lipid storage by adipocytes is a key component to adipose lipid regulation, the adipose endothelium is responsible for connecting the adipocytes to the bloodstream and is thus an essential component as well. Indeed, fatty acid flux is in part regulated by the endothelium, as the endothelium is the site of LPL lipolysis and expresses fatty acid binding proteins (such as FABP4) and fatty acid translocase CD36, which mediate transport of fatty acids across the endothelium.¹⁹ Briot et. al.²⁰ recently found that serially passaged primary human adipose tissue endothelial cells (hATECs) have decreased FA uptake at higher passages, and this decrease in FA uptake was accompanied by an increase in CDKN2A mRNA, a marker of senescence, and reduced sensitivity to rosiglitazone-stimulated FA uptake. In addition, the authors found that, while rosiglitazone suppresses inflammatory gene expression in early passage hATECs, rosiglitazone instead upregulates these genes in late passage hATECs. Altogether, these studies suggest that senescence in the adipose tissue endothelium affects fatty acid flux by modulating PPARγ action and implicates aging endothelium as a potential contributor to aging-associated adipose dysfunction. In addition, these studies raise important considerations regarding the use of PPARγ agonists as therapeutics given the different actions of PPARγ under different metabolic states.

Adipokines and Cardiovascular Risk

Adipose tissue is increasingly recognized as an endocrine organ, capable of remotely signaling to other tissues to alter their metabolic program. This signaling is accomplished through the secretion by adipocytes of numerous factors generally referred to as adipokines, and including molecules such as leptin, adiponectin, chemerin, and others. Adipokines have a wide range of metabolic effects, including the regulation of insulin sensitivity, inflammation, fibrosis, appetite, and blood pressure.²¹ Given the vast array of metabolic effects of adipokines, there is great interest in the contribution of adipokines to cardiovascular risk and multiple novel mechanisms through which adipokines contribute to coronary heart disease (CHD) have recently been described (Figure 1).

Figure 1. Summary of recent advances in roles for adipokines in cardiovascular disease.

Adipose tissue, comprised mainly of adipocytes and immune cells, exerts endocrine effects on distant tissues through the secretion of adipokines such as adiponectin and leptin. This figure highlights three novel functions for adipokines that were recently described in ATVB. A) Adiponectin receptor agonist ADP355, upon binding the adiponectin receptor AdipoR1, upregulates Ldlr through increased SREBP2-mediated transcription. ADP355 binding also upregulates hepatic Pcsk9 through increased PPARγ-mediated transcription in wild-type mice, yet downregulates Pcsk9 in ApoE −/− mice. It remains to be confirmed that adiponectin itself will exert the same effects in the liver. B) Leptin signaling via the leptin receptor (OBR) in the vasculature can modulate neointimal formation. Leptin signaling to adventitial Sca1+ progenitor cells (top) activates signaling cascades which increase migration of these cells across the vessel wall and into the neointima. In endothelial cells (bottom), leptin signaling promotes the sequestration of AP1 by PPARγ. During leptin resistance in obesity, AP1 is free to activate endothelin-1 (ET1) transcription and secretion, which in turn promotes smooth muscle cell (SMC) proliferation and neointimal formation.

Leptin was originally discovered as the satiety factor that is deficient in ob/ob mice and mediates their phenotype;²² it has since been implicated in many other physiological roles.²³ Interestingly, recent reports have suggested that leptin can directly affect neointimal formation during vascular injury such as in atherosclerosis. Hubert et. al.²⁴ demonstrated that leptin signaling can reduce neointimal formation as selectively deleting the leptin receptor (OBR or LepR) in endothelial cells results in increased neointimal formation following chemical carotid artery injury. This finding was likely mediated in part by increased expression and secretion of endothelin-1 from OBR-deficient endothelial cells, thus highlighting a potential novel therapeutic role for endothelin-1 and positing that vascular dysfunction in obesity is in part due to leptin resistance. Conversely, Xie et. al.²⁵ reported that in a vessel-wall injury model using full-body OBR knock-out mice, the loss of leptin signaling resulted in decreased migration of Sca-1+ progenitor cells to lesions post injury, thus identifying a context in which leptin signaling contributes to neointimal formation. These studies highlight opposing roles for leptin signaling in neotintimal formation that are highly dependent on the cellular context in the vessel wall, and underscore the need to investigate all relevant cell types when discussing the therapeutic potential of adipokines.

Epidemiological studies looking for associations between adipokine levels and cardiovascular disease have been useful in identifying possible roles for adipokines. One recent study by Gasbarrino et. al.²⁶ investigated the association between multiple adipokines and plaque instability and cerebrovascular symptomatology in 165 patients with coronary artery stenosis. They found that high resistin levels were associated with cerebrovascular symptomatology in patients with Type 2 diabetes (T2D), although it is worth noting that resistin, while secreted from adipocytes in rodents, is mostly produced by macrophages in humans.²⁷ Leptin also was positively associated with the formation of a carotid plaque lipid core and inflammatory cell cap infiltration, while the adipokine chemerin negatively correlated with carotid plaque instability. In a just published study, Zylla et al.²⁸ sought to determine the association of chemerin with subclinical parameters of atherosclerosis in 4000 subjects Study of Health in Pomerania (SHIP) cohort. They found that circulating chemerin levels were not associated with carotid intima-media thickness, carotid plaque, or carotid stenosis, but did inversely associate with ankle-brachial index, an indicator of peripheral artery disease. This study is the largest epidemiological study of chemerin and atherosclerotic parameters, and the results suggest that chemerin may play different roles in atherosclerosis depending on the vascular region affected and the maturity of the plaques.

With regards to cardiovascular mortality, Liu et. al.²⁹ looked at plasma levels of the adipokines FABP-4, RBP-4, and adiponectin and their association with CVD mortality in a longitudinal study of 950 men with T2D; the study showed increased cardiovascular mortality with increased serum levels of FABP-4 and adiponectin. FABP-4, secreted by both adipocytes and macrophages, has been shown to increase inflammatory cytokine signaling in macrophages, coronary artery smooth muscle cells, and vascular endothelial cells, supporting a role for the contribution of FABP-4 to CVD and atherosclerosis via vascular inflammation.³⁰

The adipokine adiponectin is the focus of a great deal of research, given its observed beneficial effects on insulin sensitivity, inflammation, hepatic lipid metabolism, and plaque formation.³¹ One major target of adiponectin signaling is the liver, which expresses two adiponectin receptors, AdipoR1 and AdipoR2. Adiponectin has been shown to suppress hepatic gluconeogenesis and to stimulate lipolysis, thus contributing to insulin sensitivity.³² Roles for adiponectin signaling in regulating hepatic cholesterol production are less clear. One study showed that treatment of rat primary hepatocytes in culture with adiponectin resulted in increased Abca1 and decreased Hmgr protein levels.³³ More recently, Sun et. al.³⁴ found that treating HepG2 human hepatoma cells with adiponectin receptor agonists results in both increased PCSK9 expression via PPARγ activation, and increased LDLR expression through activation of SREBP-2. Notably, intraperitoneal injection of an AdipoR agonist in wild-type C57BL/6 mice results in increased hepatic Pcsk9 and Ldlr as well as in decreased serum LDL-C, confirming this effect in vivo. In Apoe−/− mice, treatment with AdipoR agonist causes decreased Pcsk9 and increased Ldlr, and reduced atherosclerotic lesions by one-third. The importance of Pcsk9 for the beneficial in vivo effects of AdipoR agonists is unclear, given the different direction of effect of AdipoR agonists on PCSK9 expression between wild-type and Apoe−/− mice. Nonetheless, this study sheds light on a protective role for adiponectin signaling in atherosclerosis and LDL-C regulation.

Despite these findings, the extent of the physiologic consequences of adiponectin on cholesterol levels and CHD in humans remains less clear. Indeed, as mentioned above, Liu et al. found a positive correlation between cardiovascular mortality and plasma adiponectin levels.²⁹ That adiponectin was associated with increased cardiovascular mortality was an especially surprising finding, given that low adiponectin levels are associated with increased CHD risk.³⁵ One possible explanation for this paradox is that increased adiponectin levels are due to compensation for underlying disease. Alternatively, these findings could be due to overtreatment of subjects with lower adiponectin levels, or to confounding variables such as adipose burden, which contributes to both adiponectin levels and mortality.^36,37 Given these discrepancies, of note is another study that sought to determine a causal role for adiponectin in CHD using Mendelian Randomization, and found that genetic variants that affect circulating adiponectin levels do not associate with any change in CHD risk.³⁸ There are potential confounding factors at play in this study, highlighted by an accompanying editorial in the same issue,³⁹ but these results nonetheless raise questions about the relevance of adiponectin to CHD risk.

Adipose in the Inflamed State

Inflammation of adipose tissue, caused by obesity and metabolic disease, is a pathogenic state that can have profound consequences on adipose function and is thus the focus of a great deal of research. An aseptic and often chronic state, adipose inflammation is typically marked by an increase in the secretion of pro-inflammatory cytokines and infiltration of immune cells (quantifiable by immunohistochemistry or flow cytometry).⁴⁰ There is also accumulating evidence that inflammation plays a contributing role in the adverse effects of ectopic adipose accumulation;⁴¹ a particular example is that of intermuscular adipose tissue (an ectopic adipose depot recently found to be associated with coronary artery calcification⁴² in addition to insulin resistance⁴³), which has been associated with increased inflammatory markers.^44,45 Indeed, multiple studies have found roles for immune cells and inflammatory cytokines (such as resistin and MCP-1) in inflamed adipose tissue in the development of insulin resistance and atherogenesis.⁴⁶ As such, targeting adipose inflammation is being considered as a therapeutic strategy for obesity-related disorders,⁴⁷ though this remains controversial in light of context-specific beneficial metabolic roles for adipose inflammation.⁴⁸ A better understanding of the processes driving pathogenic adipose inflammation in metabolic disease is crucial for understanding potential applications to treatments.

Production of reactive oxygen species (ROS) has also been proposed to contribute to adipose inflammation. Overabundant lipid accumulation in adipocytes results in oxidative stress and subsequent production of ROS, which is followed by increased adipocyte expression of adipocytokines such as MCP-1, PAI-1, and IL-6, which in turn recruit macrophages and inflammatory cells to the adipose.⁴⁹ There are several sources for ROS production in adipocytes, including mitochondria and NADPH oxidases (NOX), with Nox-4 being the major NOX isoform in adipocytes.⁵⁰ While a whole-body knockout of Nox-4 results in increased diet-induced obesity, increased insulin resistance, and increased adipocyte hypertrophy and inflammation in white adipose,⁵¹ Den Hartigh et. al.⁵² found that adipocyte specific knockout of Nox-4 in mice resulted in delayed onset of both insulin resistance and adipose inflammation, with decreased initial recruitment of macrophages to adipose in the setting of a high-fat, high-sucrose diet. This study supports the notion that ROS production in adipocytes may mediate adipose inflammation as well as insulin resistance, and that inhibiting Nox-4 production of ROS may be therapeutic.

Inflammation itself necessitates the presence of inflammatory cells,⁵³ and while macrophages are perhaps the most well-studied, T-cells and B-cells can modulate adipose inflammation as well. In healthy, lean adipose, macrophages express anti-inflammatory genes (i.e. Ym1, arginase1, IL-10) in contrast to macrophages in obese adipose, which have a pro-inflammatory phenotype.⁵⁴ Remarkably, while normally accounting for only 5% of cells in lean adipose, macrophages can comprise up to 50% of cells in obese, inflamed adipose.⁵⁵ Studies suggest that T-cell infiltration of adipose occurs before macrophage recruitment during induction of adipose inflammation,⁵⁶ and T-cells are thought to contribute to macrophage recruitment in obesity.⁵⁷ Less is known about B-cell contribution to adipose inflammation, and the role of B-cells may be disease dependent. B-cells in the setting of T2D have been suggested to increase inflammation through pro-inflammatory interactions with T-cells.⁵⁸ At the same time, certain populations of B-cells are thought to repress adipose inflammation. Regulatory B-cells in healthy adipose produce anti-inflammatory cytokines, and loss of this function contributes to obesity-induced adipose inflammation.⁵⁹ Meanwhile, whole-body knockout mice of Id3, a transcription factor that has roles in B-cell development, were protected against diet-induced visceral adipose tissue (VAT) expansion.⁶⁰ A recent study of Id3 B-cell specific knockout in mice found that decreased VAT inflammation was accompanied by an increase in B1-b cell population, which secretes anti-inflammatory IgM natural antibodies,⁶¹ thus supporting an anti-inflammatory role for B1-b cells in adipose. As B-cells are found in human adipose, these studies altogether provide insight into possible inflammatory and anti-inflammatory mechanisms of B-cell roles in adipose.

Endothelial cells are known to play important roles in regulation of inflammation in general as the vascular wall serves as the point of entry for circulating leukocytes into organs. Several studies point to important roles for adipose endothelial cells in the recruitment of leucocytes and development of inflammation through processes such as expression of adhesion molecules or expression of inflammatory cytokines.⁶² The stimulator of interferon genes protein (STING), an enzyme involved in activation of the inflammatory transcription factor IRF3, was recently implicated by Mao et. al.⁶³ to be a novel player in adipose inflammation. Palmitic acid treatment of human endothelial cells induced endothelial inflammation with increased expression of ICAM-1 and monocyte-endothelial cell adhesion in a STING and IRF3-dependent manner. Furthermore, Sting-deficient mice had impaired diet-induced upregulation of phosphorylated Irf3, Icam-1 levels, and, notably, macrophage infiltration in epididymal adipose tissue compared to their wild-type counterparts, suggesting a role for Sting in macrophage recruitment to adipose through changes in adipose endothelial cells. The authors also propose a therapeutic potential for Sting as decreased adipose inflammation was accompanied by improved insulin sensitivity and glucose tolerance as well as decreased serum FFA levels and body weight in the Sting-deficient mice. In another study looking at adipose endothelial cells, Dou et. al.⁶⁴ observed increased ADAM17 in endothelial cells of aged, obese adipose from both humans and mice. Additionally, the authors found that increased adipose tissue endothelial ADAM17 may be a significant source of soluble TNFα that can contribute to development of coronary microvascular dysfunction in the settings of obesity and aging. These two studies highlight roles for non-adipocyte components of adipose tissue that contribute to the inflammatory phenotype of obesity-related disease.

Perivascular Adipose Regulation of the Vasculature

The association between obesity and coronary artery disease has engendered much interest in adipose-specific regulation of the vasculature.^65,66 In particular, perivascular adipose tissue (PVAT), which is found immediately surrounding blood vessels, has been implicated in multiple studies as a regulator of vascular function. Healthy PVAT is found in lean individuals and exerts an anti-contractile effect on vasculature. On the other hand, PVAT burden is remarkably increased in obese individuals, and dysfunction of the adipose tissue has been implicated in increased vascular contractility, inflammation, and endothelial insulin resistance.⁶⁷ Thus, dysfunctional PVAT is thought to contribute to CVD, and a better understanding of the mechanisms of PVAT regulation of vasculature may provide insight into new treatments for CVD risk factors. Several recent studies published in ATVB have identified multiple mechanisms through which PVAT regulates vasculature.

One vasodilatory mechanism in endothelial cells is through signaling of the neurotransmitter acetylcholine.^68,69 Xia et. al.⁷⁰ confirmed that PVAT is an important regulator of acetylcholine-induced vasodilation, as isolated aortas from lean and obese mice were equally sensitive to the vasodilatory effects of acetylcholine when the PVAT was removed, while leaving the PVAT resulted in a greater vasodilatory effect in the lean samples. The group further showed that these effects were mediated by endothelial nitric oxide synthase (eNOS) uncoupling in PVAT in obese mice, resulting in decreased nitric oxide (NO) signaling from the PVAT to endothelium. Norepinephrine, another neurotransmitter that regulates vascular tone, is implicated in vasoconstriction through binding of alpha receptors on endothelial cells.⁷¹ Bussey et. al.⁷² showed that PVAT in lean rats reduced norepinephrine-induced vasoconstriction while PVAT in obese rats had no anticontractile effect. Bussey et. al. further found that diet-induced weight loss after diet-induced obesity restored PVAT vasodilatory function with increases in eNOS activity. While norepinephrine generally causes vasoconstriction from direct interaction with endothelium, Saxton et. al.⁷³ recently confirmed the theory that norepinephrine signaling to PVAT results in a vasodilatory effect that is in part due to increased adiponectin secretion and signaling to local vessels. Electric field stimulation of explanted PVAT from mice resulted in increased adiponectin secretion into the surrounding solution, and that increase was dependent on B₃-adrenoreceptor activation. Furthermore, transferring the conditioned solution to PVAT-denuded vessels induced a vasodilatory effect, showing that a secreted factor is responsible for the anticontractile effect. The anticontractile effect of PVAT was both blunted by treatment of PVAT-surrounded vessels with an adiponectin-blocking peptide, and completely abrogated by using PVAT from adiponectin knockout mice. These data strongly point to adiponectin being a mediator of the vasodilatory effect of norepinephrine on PVAT.

Not all PVAT is solely comprised of white adipose tissue; various PVAT depots are comprised of brown (BAT) and/or beige adipose tissue (BeAT). Friederich-Persson et. al.⁷⁴ found that these different types of PVAT depots in mice have different mechanistic vasodilatory roles. In a series of wire-myography experiments where vascular contractility was measured in the presence of white, beige, or brown PVAT, brown adipose was found to both decrease the contractile capacity of vasculature and decrease sensitivity to the vasoconstrictive effects of norepinephrine to a higher extent than white or beige adipose. The group additionally identified molecular mechanisms in brown adipose (Nox-4-mediated H₂O₂ production) that contributed to vasodilation that were not significant in white or beige adipose. These observations highlight the complex roles that different adipose depots have with respect to PVAT function, and in particular shine attention on novel roles for brown and beige PVAT as a mediator of vascular function.⁷⁵

Several studies report that inflammatory changes in PVAT result in a change in PVAT signaling which causes increased vascular contractility.⁷⁶ Candela et. al.⁷⁷ found that adipocytes from PVAT from lean and obese mice had comparable vasodilatory effects, suggesting that impaired vasodilation in obesity is not solely dependent on adipocytes. Notably, an increased inflammatory macrophage population was observed in obese PVAT, and co-culture studies of arterioles with macrophages from lean and obese mice suggested that impaired vasodilation was in part mediated by increased macrophage iNOS activity that mediated decreased endothelial/smooth muscle hydrogen-sulfide levels. Although the macrophages used in the co-culture experiments were derived from mesenteric adipose, these are thought to be similar in phenotype to macrophages found in PVAT. Thus, this study supports the possibility that inflammatory resident cells in PVAT are direct modulators of PVAT regulation of endothelium. Additionally, Ohyama et. al.⁷⁸ found that inflammation in PVAT following the placement of an everolimus-eluting stent, a drug-eluting stent, is associated with coronary hyperconstrictive responses in pigs, suggesting that PVAT inflammation and associated dysfunction may contribute to adverse effects following stent placement.

Not only is PVAT implicated in regulating vasculature contractility, but it also is actively studied as a contributor to atherogenesis; indeed, vasoconstriction and endothelial dysfunction can play a role in the etiology of vascular damage and are considered risk factors for atherosclerosis.⁷⁹ Thus, understanding the molecular mechanisms leading to PVAT dysfunction and inflammation can provide insight into potential treatments for reducing atherosclerotic risk. Konaniah et. al.⁸⁰ studied the adipocyte-specific role of the low-density lipoprotein receptor-related protein-1 (Lrp1), and found that adipocyte-specific deletion of Lrp1 results in increased adipose inflammation. Moreover, transplanting Lrp1−/− PVAT tissue into wild-type mice resulted in a 3-fold increase in atherosclerosis compared to transplanting Lrp1+/+ PVAT tissue. Chen et. al.⁸¹ recently published evidence that Vitamin D inhibits NF-kB-mediated inflammatory signaling in preadipocytes. Further studies comparing swine fed Vitamin D sufficient or deficient high-cholesterol diets revealed increased stenosis in Vitamin D deficient swine. In addition, Vitamin D deficiency was accompanied by increased KPNA4 and NF-kB transcriptional activity in epicardial adipose tissue, a depot of PVAT. Altogether, these recent studies confirm important roles and physiologic relevance of PVAT, and therapeutic strategies targeting this adipose depot, whether it be through lifestyle changes (weight-loss or vitamin D supplementation) or by targeting molecular mechanisms, may hold promise.

Summary

Once thought to be a simple storage depot for fat, adipose is now recognized as a dynamic tissue with myriad roles in human metabolism, health, and disease pathophysiology. Publications during the past two years in ATVB reveal new directions in adipose research pertaining to mechanisms of lipid regulation, local and systemic effects of adipokine signaling, mediators of adipose inflammation, and a relatively new concept of PVAT regulation of vasculature and atherosclerosis. A better understanding of adipose biology, both in the healthy and diseased state, may ultimately aid in efforts to develop improved therapies for obesity-related diseases such as cardiovascular disease.