Development of metabolic dysfunction in mice lacking chemerin
Introduction
Obesity and overweight are important risk factors for the development of type 2 diabetes, fatty liver disease, dyslipidemia, insulin resistance and cardiovascular disease (Shannon et al., 2020; Kubota et al., 2017). Although the etiology of obesity related metabolic comorbidities is not fully clear, it is recognized that obesity frequently leads to a dysregulation of adipokine secretion, which play important roles in the regulation of fat distribution, insulin sensitivity and insulin secretion and energy expenditure (Blüher, 2014).
Chemerin, encoded by the gene Rarres2, was initially identified as a tazarotene induced protein in the skin (Kutzleb et al., 2005). It is highly expressed in adipose tissue, liver, placenta, intestine, pancreas, adrenal gland and ovary (Helfer and Wu, 2018). Chemokine-like receptor 1 (CMKLR1) and G protein-coupled receptor 1 (GPR1) have been identified as receptors for chemerin in vitro (Ernst and Sinal, 2010). Extracellular proteolytic processing of chemerin generates a spectrum of isoforms that differ significantly with respect to the ability to activate the cognate receptors CMKLR1 and GPR1 (Buechler et al., 2019).
Numerous studies have evaluated chemerin effects on glucose metabolism (Roman et al., 2012; Helfer and Wu, 2018). On the one hand, the majority of clinical data showed that the higher plasma total chemerin levels were found in patients with metabolic syndrome, obesity and type 2 diabetes (Akgul et al.,2019; Kim et al., 2014). The concentrations of the chemerin isoforms chemerin-163, chemerin-157, and chemerin-155 were, however, not markedly changed in the overweight individuals or in obesity, suggesting that higher chemerin protein in obesity was not linked to increased chemerin bioactivity (Buechler et al., 2019; Chang et al., 2016). Besides, chemerin levels were positively correlated with body fat, glucose, lipid metabolism, and inflammation, suggested that this adipokine played a role in the pathophysiology of obesity and metabolic syndrome (Akgul et al.,2019; Kim et al., 2014).
On the other hand, chemerin seems to also have beneficial effects on glucose uptake and insulin sensitivity under conditions of type 2 diabetes. Firstly, treatment of 3T3-L1 adipocytes and primary mouse epididymal adipocytes with 6 nM chemerin for 12 h resulted in an increase in insulin-stimulated glucose uptake in vitro (Takahashi et al., 2008; Wargent et al., 2015). In vivo, plasma levels of total chemerin, chemerin-157 and chemerin-156 were markedly increased in the 12-weeks high fat diet fed mice (Haberl et al., 2018; Buechler et al., 2019; Huang et al., 2020). The chemerin and CMKLR1 knockdown decreased insulin-stimulated glucose uptake and GLUT4 expression in adipocyte and myocyte compared with vehicle control (Goralski et al., 2007; Wargent et al., 2015). In addition, GPR1 knockdown enhanced glucose intolerance and decreased β-cell proliferation and insulin levels in high-fat diet-fed pregnant mice (Huang et al., 2019).
Furthermore, chemerin treatment exacerbates glucose intolerance in obese/diabetic mice, but not normoglycemic models by decreasing serum insulin levels, reducing adipose tissue glucose uptake and causing a significant decrease in liver and total tissue glucose uptake (Ernst et al., 2010). Moreover, chemerin, CMKLR1 and GPR1 knockout mice displayed hyperglycemia, reduced glucose stimulated insulin release and impaired glucose tolerance compared to wild type mice when fed on either a low- or a high-fat diet, while chemerin transgenic mice exhibited enhanced insulin secretion in glucose tolerance tests (Rourke et al., 2014; Ernst et al., 2012; Takahashi et al., 2011; Huang et al. 2016, 2020).
Although there is consensus that chemerin regulates glucose homeostasis, its role in regulating glucose metabolism remains unclear owing to the conflicting findings derived from various in vivo and in vitro studies (Kralisch et al., 2009; Sell et al., 2009). For example, in contradiction to results mentioned above, treatment with chemerin resulted in an increase of insulin receptor substrate (IRS)1 tyrosine phosphorylation and a decrease in insulin-stimulated glucose uptake in 3T3-L1 adipocytes and primary human skeletal muscle cells (Kralisch et al., 2009; Sell et al., 2009). In addition, CMKLR1 deficiency did not affected the glucose tolerance and insulin sensitivity of mice fed a high-fat diet (Gruben et al., 2014). These reports suggest that chemerin might also play a role in metabolism through receptors other than CMKLR1. Therefore, further studies are required to clarify the role of chemerin in glucose metabolism.
In this study, through the global rarres2 knockout mice fed on either a low- or a high-fat diet, we addressed the effect of chemerin on glucose metabolism in vivo.
Section snippets
Drugs and reagents
Trizol reagent (Cat. No. R401-01) was acquired from Vazyme Biological Technology Corporation, Nanjing, China. RIPA lysis buffer (Cat. No. 01408/30,450) was acquired from KangWei Century Corporation, Beijing, China. Antibody against β-actin (Cat. No. bs-0061R) was acquired from Boaoseng, Beijing, China. Antibodies against peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) (Cat. No. ST-1202) and GLUT4 (Cat. No. 07–1404) were acquired from Merck Millipore Inc, Germany. Antibody
Chemerin reduces fasting blood glucose and improves glucose homeostasis
To evaluate the role of chemerin in glucose homeostasis, the body weight, fasting blood glucose, GTT and ITT were collected in Rarres2−/− mice fed with a chow diet compared with WT mice fed with a chow diet. As shown in Fig. 1A, we did not observe significant variation of body weight in Rarres2−/− mice compared with WT mice fed with a chow diet. Our results showed that fasting blood glucose was significantly increased in Rarres2−/− mice compared with WT mice fed with a chow diet (Fig. 1B).
Discussion
Chemerin, an adipocyte-secreted adipokine, is reported to participate in energy homeostasis and glucoregulation. The previous studies showed that there were positive relations between serum chemerin level and body fat, glucose as well as lipid levels in obese and diabetic patients (Akgul et al.,2019; Kim et al., 2014). Besides, abrogation or knockdown of chemerin decreased insulin-stimulated glucose uptake and glucose tolerance (Goralski et al., 2007; Wargent et al., 2015). Consistent with
Author contributions
Penghua Fang and Wen Min conceived and designed the experiments. Long Han, Mei Yu, Shiyu Han, Mengyuan Wang, Yujie Huang and Wancheng Guo performed the experiments. Long Han, Shiyu Han, Qingbo Wei and Mei Yu analyzed the data. Wenbing Shang, Penghua Fang and Wen Min contributed reagents/materials/analysis tools. Penghua Fang and Wen Min wrote the manuscript.
Conflicts of interest
The authors have no conflicts of interest to disclose.
Acknowledgement
This work was supported by the National Natural Scientific Fund of China (No. 81803792; No. 81774335) and the Youth Project of Natural Scientific Fund of Nanjing University of Chinese Medicine (No. NZY81803792) and Nursing advantage discipline funding project of Jiangsu Province university (No.2019YSHL081) and A project funded by the priority academic program development of Jiangsu Higher Education Institutions (No. ZYX03KF058).
References (36)
- et al.
Exercise stimulates Pgc-1 alpha transcription in skeletal muscle through activation of the p38 MAPK pathway
J. Biol. Chem.
(2005) Adipokines - removing road blocks to obesity and diabetes therapy
Mol Metab
(2014)- et al.
Chemerin: at the crossroads of inflammation and obesity
Trends Endocrinol. Metabol.
(2010) - et al.
Chemerin, a novel adipokine that regulates adipogenesis and adipocyte metabolism
J. Biol. Chem.
(2007) - et al.
Ex vivo analysis of serum chemerin activity in murine models of obesity
Cytokine
(2018) - et al.
CMKLR1 deficiency influences glucose tolerance and thermogenesis in mice on high fat diet
Biochem. Biophys. Res. Commun.
(2016) - et al.
Interleukin-1 beta induces the novel adipokine chemerin in adipocytes in vitro
Regul. Pept.
(2009) - et al.
Imbalanced insulin actions in obesity and type 2 diabetes: key mouse models of insulin signaling pathway
Cell Metabol.
(2017) - et al.
Chemerin enhances insulin signaling and potentiates insulin-stimulated glucose uptake in 3T3-L1 adipocytes
FEBS Lett.
(2008) - et al.
Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1
Cell
(1999)
Irisin and chemerin levels IN patients with type 2 diabetes mellitus
Acta Endocrinol.
Chemerin isoforms and activity in obesity
Int. J. Mol. Sci.
Chemerin activation in human obesity
Obesity
Disruption of the chemokine-like receptor-1 (CMKLR1) gene is associated with reduced adiposity and glucose intolerance
Endocrinology
Chemerin exacerbates glucose intolerance in mouse models of obesity and diabetes
Endocrinology
Chemokine-like receptor 1 deficiency does not affect the development of insulin resistance and nonalcoholic fatty liver disease in mice
PloS One
Chemerin: a multifaceted adipokine involved in metabolic disorders
J. Endocrinol.
Impact of GPR1 signaling on maternal high-fat feeding and placenta metabolism in mice
Am. J. Physiol. Endocrinol. Metab.
Cited by (9)
Adipose–Muscle crosstalk in age-related metabolic disorders: The emerging roles of adipo-myokines
2023, Ageing Research ReviewsCitation Excerpt :Therefore, figuring out the precise biological process by which insulin resistance leads to diabetes would make it easier to develop novel therapeutics to ward off the disease. More recently, there has been a considerable body of evidence supporting the notion that cytokines protect against many serious chronic low-grade inflammatory disorders, including type 2 diabetes, obesity, and the metabolic syndrome (Kim et al., 2019; Ren et al., 2022; Fang et al., 2021a, 2021b). The idea that adipocytes are important secretory cells that release adipokines has recently attracted increased attention (Fang et al., 2021a, 2022a).
Adipose tissue spexin in physical exercise and age-associated diseases
2022, Ageing Research ReviewsCitation Excerpt :Decreased serum chemerin concentrations have been reported in obese humans as a response to an acute bout of aerobic exercise or 24 weeks of exercise (Lloyd et al., 2016; Lakhdar et al., 2019). From a metabolic point of view, chemerin has functions in increasing insulin-stimulated glucose uptake and GLUT4 protein expression in adipocytes and myocytes of mice (Fang et al., 2021). Specifically, chemerin knockout mice showed elevated fasting glucose levels and glucose intolerance as well as insulin intolerance (Fang et al., 2021).
Editorial for special issue on “Endocrinology of adipokines“
2022, Molecular and Cellular EndocrinologyProgress in the contrary effects of glucagon-like peptide-1 and chemerin on obesity development
2023, Experimental Biology and MedicineChemerin: A Functional Adipokine in Reproductive Health and Diseases
2022, Biomedicines
- 1
Co-first author.