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Tan, L.; Lu, X.; Danser, A.H.J.; Verdonk, K. Role of Chemerin in Metabolic and Cardiovascular Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/46115 (accessed on 25 June 2024).
Tan L, Lu X, Danser AHJ, Verdonk K. Role of Chemerin in Metabolic and Cardiovascular Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/46115. Accessed June 25, 2024.
Tan, Lunbo, Xifeng Lu, A. H. Jan Danser, Koen Verdonk. "Role of Chemerin in Metabolic and Cardiovascular Disease" Encyclopedia, https://encyclopedia.pub/entry/46115 (accessed June 25, 2024).
Tan, L., Lu, X., Danser, A.H.J., & Verdonk, K. (2023, June 27). Role of Chemerin in Metabolic and Cardiovascular Disease. In Encyclopedia. https://encyclopedia.pub/entry/46115
Tan, Lunbo, et al. "Role of Chemerin in Metabolic and Cardiovascular Disease." Encyclopedia. Web. 27 June, 2023.
Role of Chemerin in Metabolic and Cardiovascular Disease
Edit

Chemerin is a novel adipokine that plays a major role in adipogenesis and lipid metabolism. It also induces inflammation and affects insulin signaling, steroidogenesis and thermogenesis. Consequently, it likely contributes to a variety of metabolic and cardiovascular diseases, including atherosclerosis, diabetes, hypertension and pre-eclampsia.

chemerin nutrients cardiovascular disease metabolic disease

1. Introduction

Over the last three decades, due to the obesity epidemic, attention has shifted to achieving an improved energy balance. The underlying concept is that a healthy lifestyle and well-controlled nutrition will avoid obesity, and consequently prevent the development of metabolic syndrome and any resulting cardiovascular disease [1].
Chemerin is a multifunctional protein that has recently been identified as an essential player in hypertension, myocardial infarction, preterm birth, diabetes, metabolic disease and liver cirrhosis [2][3]. In the two decades since its initial discovery, more than a thousand articles have been published on chemerin [4], but none reviewed its relationship with nutrition.

2. Potential Role of Chemerin in Metabolic and Cardiovascular Disease

2.1. Lipid Metabolism

Chemerin not only stimulates adipogenesis but also facilitates lipid accumulation in a wide variety of cells [5][6][7][8][9][10]. In agreement with this concept, its levels and receptors are upregulated in differentiating preadipocytes. Moreover, obesity, NAFLD and nonalcoholic steatohepatitis (NASH) are all accompanied by elevated chemerin levels, while attenuating these conditions lowers chemerin [11][12][13][14]. Table 1 summarizes the genes that are currently believed to be involved in the effects of chemerin on lipid metabolism. Here, it should be noted that a methionine–choline-deficient (MCD) diet (a classical dietary model of NASH) has also been reported to decrease CMKLR1 [14][15] and chemerin in the liver [16]. These opposing effects on chemerin might relate to sex, as increased chemerin levels were observed in male animals exposed to a MCD diet [17], while MCD-fed females displayed chemerin lowering [16]. Moreover, in hepatocytes or matured adipocyte cells, the fatty acids EPA, docosahexaenoic acid, palmitate acid and oleic acid all induced lipid accumulation, while only the latter increased chemerin expression, with the former three decreasing this expression [14][16][18]. In an oral lipid tolerance test, chemerin decreased when switching from fasting to lipid uptake, reaching its lowest level after 4 h [19].
Table 1. Genes and proteins that are involved in the effect of chemerin on lipid metabolism.
An obesogenic diet increases chemerin secretion from brown adipocytes, while cold stimulation caused the opposite [30][31]. Chemerin might contribute to temperature regulation, given that its overexpression decreased whole body and brown adipose tissue temperature in mice [32]. Chemerin overexpression additionally impaired metabolic homeostasis and induced glucose intolerance. These effects involved CMKLR1 and uncoupling protein 1. In addition, the chemerin–CMKLR1 axis is a physiological negative regulator of thermogenic beige fat, and targeting this pathway might be a novel strategy for obesity [33].
Circulating chemerin correlates positively with low-density lipoprotein (LDL) and negatively with high-density lipoprotein (HDL) [34][35]. Yet, the latter negative association particularly concerns large HDL, since a positive association was observed with both small and intermediate HDL. This suggests that chemerin is involved in the HDL maturing process [35][36]. LDL apheresis lowered circulating chemerin, implying that chemerin is bound, at least partly, to lipoproteins [37]. Future studies should investigate this possibility.

2.2. Cardiovascular Effects

Chemerin levels are elevated in multiple cardiovascular diseases (Table 2) [38][39][40][41]. Chemerin is not only an independent risk factor for arterial stiffness [42], but in chronic kidney disease it also is a predictive marker of atherosclerosis [43][44]. This relates to the above-described effects of chemerin on the atherogenic process, involving vascular remodeling, lipid deposition and inflammation [45][46][47][48]. Indeed, the expression of chemerin and its receptor CMKLR1 in periaortic and pericoronary fat and foam cells determines atherosclerosis severity [49][50] and correlates with carotid plaque instability [51].
Recent data suggest that chemerin also exerts effects in cardiomyocytes, vascular smooth muscle cells, endothelial cells and fibroblasts, and might even originate from some of these cells. Tumor necrosis factor-α upregulated chemerin in murine cardiomyocytes, and in these cells chemerin induced apoptosis by activating caspase 9 and reducing protein kinase B (AKT) [52]. In rat cardiac fibroblasts, chemerin promoted cell migration by increasing reactive oxygen species (ROS), AKT and ERK1/2 [53]. Aldosterone induced chemerin synthesis in cardiac fibroblasts via Rho/ROCK/JNK signaling [54]. In endothelial cells, chemerin promoted angiogenesis and ROS production and decreased insulin signaling and nitric oxide production [2][55][56].
Vascular chemerin most likely originates from perivascular adipose tissue (PVAT), while CMKLR1 occurs in endothelial and vascular smooth muscle cells [57][58]. Exogenously added chemerin induced constriction via CMKLR1, Gi and calcium in isolated vessels, and this was enhanced after endothelial removal or during nitric oxide inhibition [57][59]. Without exogenous chemerin, endogenous chemerin derived from PVAT is also capable of inducing constriction, most likely by activating the sympathetic nervous system [58]. Remarkably, although both whole-body and hepatic chemerin knockdown abolished circulating chemerin [60], only whole-body knockdown also lowered blood pressure. This implies that chemerin from a non-hepatic source, most likely PVAT, contributes to blood pressure. To what degree the chemerin-induced upregulation of inflammatory cytokines in vascular smooth muscle cells [61] contributes to vessel contraction remains unknown.

2.3. Pregnancy-Related Problems

Chemerin is also a major player during pregnancy. Circulating chemerin levels normally fall in the first and second trimesters of pregnancy, and then increase during the third trimester, reaching the highest levels at late gestation, to fall again to pre-pregnancy levels shortly after delivery [62][63][64]. The placenta is a major contributor to this rise in circulating chemerin [8]. Since cord blood chemerin levels exceed those in maternal blood [63], maternal and fetal chemerin levels may act independently. Yet, maternal obesity is associated with higher cord blood chemerin levels [65][66]. How chemerin upregulation during pregnancy is regulated and whether chemerin affects the fetus are unknown.
The high levels of chemerin in late pregnancy are suggestive of the possibility that they play a role in the preparation of delivery. This might require a delicate balance, given that overexpression of chemerin increases the risk of miscarriage [8]. Simultaneously, chemerin correlates positively with platelet count, which is relevant at the time of delivery to prevent hemorrhage [67][68][69]. Overall, excessively high maternal chemerin levels are indicative of a negative pregnancy outcome and a low birthweight, while cord blood chemerin levels associate positively with fetal birthweight [8][70][71]. In agreement with the former, intraperitoneal application of chemerin to pregnant mice with diabetes resulted in cognitive disorder in the offspring [72]. In the fetus, chemerin is expressed at the level of the intestine, where it peaks at 20–24 weeks of gestation to promote macrophage recruitment for gut development [73]. Thereafter intestinal chemerin expression returns to low levels.
Serum chemerin is increased in pre-eclampsia, correlating with the severity of the disease and adverse neonatal outcomes [71][74]. In fact, its level in the first trimester may help to predict the occurrence of pre-eclampsia [75]. Importantly, the pre-eclamptic placenta releases more chemerin than a healthy placenta [8], supporting the concept that circulating chemerin in pregnancy is placenta-derived, and that the elevated chemerin levels in pre-eclamptic women originate in the placenta. Moreover, placental chemerin overexpression in mice induced a pre-eclampsia-like syndrome, characterized by high blood pressure, proteinuria, endothelial dysfunction and fetal growth restriction [8]. Placental chemerin overexpression simultaneously increased the circulating and placental levels of cholesterol, raising the possibility that chemerin might also contribute to dyslipidemia in pre-eclampsia [76]. A rat model of pre-eclampsia similarly displayed higher circulating chemerin levels [77]. In gestational diabetes mellitus (GDM), chemerin correlates with obesity and glucose homeostasis [78]. Yet, chemerin levels in the blood, adipose tissue and placenta are not necessarily elevated in GDM [79][80]—this may be limited to obese GDM women [81][82]. In such women, high cord blood chemerin levels were predictive for both maternal insulin resistance and large for gestational-age babies [65][66]. It is important to stress that adverse perinatal outcomes are linked to maternal cardiometabolic and neurocognitive outcomes [83][84]. This may represent the long-term consequences of inflammatory dysfunction, potentially involving chemerin.

2.4. Sex Differences

Sex hormones likely contribute to the synthesis and effects of chemerin. In humans, serum chemerin increases with age, and chemerin levels are higher in females than in males [19][85]. However, in type 2 diabetes and obesity cohorts, serum chemerin in males was higher than in females [86][87]. In the deoxycorticosterone acetate–salt rat model, chemerin deletion decreased blood pressure in females while increasing blood pressure in males [88]. Furthermore, chemerin levels in white adipose tissue were downregulated in female rats and upregulated in male rats after gonadectomy [89]. The latter coincides with observations in differentiated 3T3-L1 adipocytes, where testosterone decreased chemerin release into the supernatant. Yet in these cells estradiol was without effect [19], and in lean women with polycystic ovarian syndrome (PCOS), chemerin levels were upregulated versus obese PCOS women [90]. Chemerin was observed to suppress follicular steroidogenesis and may thus contribute to PCOS [90][91]. Additionally, chemerin levels were low in subfertile males, most likely due to their elevated luteinizing hormone levels [92], and this was suggested to reflect a link between chemerin and reproductive function.
Table 2. Circulating chemerin in various metabolic and cardiovascular diseases.
Country Population Number of Included Patients (n) Chemerin Levels (ng/mL) BMI Age Reference
Control Diseased Control Diseased Control Diseased
USA Obesity 10 37 76.2 147 <25 >25 54 [93]
Hungary Obesity 50 50 405 590 <25 >25 43 [34]
Mauritius T2D 142 114 249 250 ≤25 >25 49 [94]
Saudi Arabia T2D 38 41 89 99 >25 >25 44 [77]
Germany T2D 29 29 191 219 >25 >25 56 [11]
USA T2D 969 173 180 191 >25 >25 45 [82]
China Atrial fibrillation 146 256 107.74 133.24 <25 <25 60 [38]
China Coronary artery disease 191 239 45.7 48.7 ≤25 ≤25 62 [39]
China Coronary artery disease 56 132 90 111 <25 <25 62 [40]
China Coronary artery disease 50 50 133 189 ≤25 ≤25 60 [47]
Korea Obesity and arterial stiffness 35 33 106 120 <25 >25 52 [41]
Canada Stable and unstable carotid atherosclerotic plaque   165   208   >25 70 [51]
Austria Hypertension * A total of 495 155 180 >25 65 [43]
T2D * 170 192
MetS * 163 201
Netherlands Pre-eclampsia 29 30 149 287 ≤25 ≤25 32 [8]
Germany Pre-eclampsia 37 37 205 250 <25 <25 30 [62]
Turkey Pre-eclampsia 46 88 200 358 >25 >25 27 [71]
China Pre-eclampsia 477 41 181 312 <25 ≤25 26 [75]
Germany GDM 80 40 218 230 <25 <25 30 [80]
Abbreviations. T2D, type 2 diabetes; MetS, metabolic syndrome; ACE, angiotensin-converting enzyme; AT1, angiotensin II type 1; GDM, gestational diabetes mellitus. * these three populations are from one cohort.

 

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