Adropin as an indicator of T2DM and its complications

Hu Zhng, Ning Chen*

a Graduate School, Wuhan Sports University, Wuhan 430079, China

b Tianjiu Research and Development Center for Exercise Nutrition and Foods, Hubei Key Laboratory of Exercise Training and Monitoring,College of Health Science, Wuhan Sports University, Wuhan 430079, China

ABSTRACT

Type 2 diabetes mellitus (T2DM) is one of metabolic diseases with the major inducer of obesity. Due to the change in lifestyle and dietary structure, more and more people are being suffered from T2DM. Therefore,the prevention and treatment of T2DM and its complications has become an urgent problem to be solved. As a secreted peptide, adropin is identified as a useful regulator associated with insulin sensitivity and energy homeostasis. It has the potential for regulating metabolic diseases including obesity and T2DM. It should be noted that the secretion of adropin can be induced by diets, aerobic exercise and other interventions. In this article, the underlying mechanisms of adropin for regulating obesity, T2DM and its complications including diabetic nephropathy, diabetic retinopathy, diabetic encephalopathy, diabetic vascular disease and diabetic cardiovascular disease were summarized. Meanwhile, the strategies for promoting the secretion of adropin were also discussed, which will provide a target for the prevention and targeted treatment, or a candidate of novel and effective functional food or drug for metabolic diseases in the future.

Keywords:

Adropin

Metabolic disease

Obesity

T2DM

Diabetic complications

1. Introduction

In the mid-1990s, the prevalence of diabetes in adults reveals an increase by three times during the past decade in China [1]. By 2025,approximately 80% of patients with type 2 diabetes mellitus (T2DM)will be diagnosed in developing or low- and middle-income countries [2].The morbidity and mortality of people with diabetes mellitus at different ages also exhibit an increasing trend [3].

Adropin exists in multiple tissues and organs of the body and may be closely associated with obesity and T2DM by participating in the regulation of energy metabolism and insulin resistance through G protein-coupled receptor 19 (GPR19) on cell membrane [4].Increasing experimental studies have shown that the level of adropin in healthy obese people and metabolic syndrome patients present a declining trend when compared with healthy people, and the level of adropin in patients with metabolic syndromes is much lower than the people with obesity [5]. In contrast, the deficient generation and secretion of adropin may induce obesity, insulin resistance (IR),metabolic syndrome and steatosis. As us well known, controlling diets, adjusting diet structure and increasing exercise amount are important strategies to prevent and treat metabolic diseases associated with obesity. Growing evidence has demonstrated that the appropriate exercise and diet regulation can also promote the secretion of adropin,and may be used as a potential strategy for the prevention and treatment of obesity and T2DM [6,7]. In this article, the potential mechanisms of adropin for the prevention and treatment of obesity, T2DM and corresponding complications including diabetic nephropathy, diabetic retinopathy, diabetic enacephalopathy, diabetic vascular diseases and diabetic cardiovascular diseases were summarized. Meanwhile, the targeted strategies for promoting the secretion of adropin were also discussed, which will provide a target for the prevention and targeted treatment, or a candidate of developing novel and effective functional foods or drugs for metabolic diseases in the future.

2. The discovery of adropin

Adropin is initially discovered in obese mice with melanocortin-3 receptor deficiency [1]. The name of adropin is derived from the Latin root “aduro” with the meaning of “ignited” and “pinquis” with the meaning of “fat” or “oil”, indicating the combinatorial meaning of “accelerated burning of fat” through changing adipose types and non-shivering thermogenesis in brown adipose tissues. Adropin is a secreted protein composed of 76 amino acids that plays an important role in regulating energy metabolism, and the active part of adropin is located in 34–76 residues encoded with energy homeostasisassociated gene (ENHO) [8]. The deficiency of adropin can induce several kinds of diseases including autoimmune diseases, obesity,T2DM and its complications. Adropin can be expressed in a series of tissues and organs such as pancreas, liver, kidney, brain, heart,skeletal muscle and small intestine, with the dominant expression in liver, and the expression of adropin-related gene ENHO is decreased in obese people induced by long-term high-fat diet (HFD) [9]. The secretion of adropin reveals a decreasing trend as the extension of age [7]. Currently, adropin has gained extensive attention due to its preventive and therapeutic potential for T2DM, hypertension, cerebral hemorrhage, and cognitive impairment.

3. Obesity and T2DM

Obesity is one of the major inducers of T2DM and long-term intake of foods with excessive energy will cause obesity and the overloading and functional failure of islet β cells, thus leading to insufficient secretion of insulin and accelerating the progression of T2DM. A sustained positive energy balance can produce a proinflammatory response, which is a critical factor for metabolic diseases such as T2DM and pancreatic steatosis. Obesity is also considered as a chronic in flammation with the induced in flammatory factors such as interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-α), and can inhibit interleukin-10 (IL-10)and secreted frizzed-related protein 5 (SFRP5) as one of c-Jun N-terminal kinase (JNK) inhibitors involved in the progression of insulin resistance [10,11]. High expression of TNF-α in adipose tissue can suppress the expression of glucose transporter 4 (GLUT4),insulin receptor and insulin receptor substrate 1 (IRS-1), inhibit the activation of downstream phosphatidylinositol-3 kinase (PI3K)and protein kinase B (PKB/Akt) in insulin signal pathway, thereby inducing insulin resistance [12]. In short, obesity stimulates the production of in flammatory factors, and inhibiting the generation of anti-in flammatory factors and SFRP5, thereby contributing to insulin resistance and accelerating the progression of obesity and T2DM; on the other hand, adropin rescues these abnormal regulation signalings to alleviate the progression of obesity and T2DM through adropinmediated GRP19 signal pathways (Fig. 1).

Fig. 1 The molecular mechanisms of adropin for the prevention and treatment of obesity and T2DM. Obesity can induce T2DM by increasing in flammatory factors and free fatty acids, and reducing anti-in flammatory factors and adiponectin. However, adropin can suppress the development of obesity by regulating glycolipid metabolism, and also can prevent and improve T2DM by promoting the production of anti-in flammatory factors, promoting the generation of nitric oxide (NO), and reducing insulin resistance.

4. Adropin and obesity

Nowadays, obesity has become a global health issue due to the imbalanced uptake and consumption of calories. As a chronic inflammation, obesity can lead to dyslipidemia, insulin resistance,cardiovascular diseases, and other complications. Previous studies have demonstrated that HFD feeding can lead to excessive β-oxidation,fatty acid overloading and low-level inflammation [9]. Long-term inflammation can lead to insulin resistance and promote hepatic gluconeogenesis, which will aggravate the progression of metabolic syndrome and T2DM [13]. Although relevant studies have shown that the increased generation and secretion of adropin can promote the proliferation of pre-adipocytes, adropin can attenuate the differentiation of these pre-adipocytes into mature adipocytes [14],which may be due to that adropin down-regulates the transcription and expression of lipid synthesis-related gene peroxisome proliferatoractivated receptor-γ (PPAR-γ) and its regulatory genes in liver and adipose tissue [9]. In addition, adropin can reduce the activity of JNK and protein kinase A (PKA) to suppress the phosphorylation of cAMP-responsive element-binding protein (CREB), and improve insulinmediated glucose homeostasis-related signal pathways, thus affecting the metabolism of primary mouse hepatocytes [15]. Under the environment with various nutritional conditions, adropin can activate pyruvate dehydrogenase (PDH) by inhibiting pyruvate dehydrogenase kinase 4 (PDK4), suppress carnitine palmitoyltransferase-1B (CPT-1B),and promote the oxidation of carbohydrates through regulating the acetylation of proliferator-activated receptor gamma coactivator-1 α (PGC-1α) to improve the utilization rate of glucose in skeletal muscle, reduce blood glucose and restore insulin sensitivity [16,17].Simultaneously, adropin can influence mouse motor movement and body coordination by integrating with brain-specific Notch1 ligand NB3 to control energy expenditure [18]. The mice with ADROPIN knockout reveal the increase in fat deposition by 50% in spite of normal food intake, and the ratio of adropin and leptin in people with obesity is also much lower than normal population [5,19]. Moreover,the low expression levels of ENHO gene and adropin are also the essential factors for inducing obesity, and the change of adropin level may be a potential indicator for predicting obesity and obesity-related diseases, such as T2DM [9,20,21]. According to the close relationship between obesity and adropin demonstrated in current studies, targeted interventions of adropin could be beneficial for the prevention and treatment of obesity in the future.

5. Adropin and T2DM

With the changes in lifestyle and habits, the number of patients with T2DM is increasing, even in teenagers [22]. Long-term maintenance of high blood glucose level in diabetic patients will lead to a series of complications such as diabetic nephropathy and diabetic cardiovascular disease. The major cause of the currently known T2DM is the relative deficiency of insulin secretin or insulin resistance due to inappropriate lifestyle, and dysfunctional genetic regulation,endocrine and intestinal flora [23,24]. The binding of IRS-1 to PI3K during normal metabolism can activate 3-phosphoinositidedependent protein kinase 1 (PDK1) and downstream Akt. Activated PDK1 can accelerate the uptake of glucose via GLUT4 in skeletal muscle, thereby lowering blood glucose. Insulin resistance is also due to the down-regulated IRS-1/2 and dysfunctional signal pathways,thus leading to low capability or incapability of GLUT4 to properly uptake and translocate glucose. In human trials, by comparing with the body mass index (BMI) of healthy population, based on the correlation analysis among high-sensitivity C-reactive protein (hs-CRP),triglyceride (TG), fasting blood glucose (FPG), insulin resistance index (HOMA2-IR), glycated hemoglobin (HbA1c) and high-density lipoprotein cholesterol (HDL-C), adropin has a significant correlation with T2DM [25]. Similarly, recent studies have also confirmed that adropin secreted mainly by liver is also closely correlated with nonalcoholic fatty liver disease (NAFLD) [26,27]. Adropin has antiin flammatory and anti-oxidant effects in the liver, which can reduce liver damage and the incidence of T2DM [28-30]. Besides, adropin can activate AMPK by inhibiting protein phosphatase 2A (PP2A) in insulin-resistant liver cells to reduce glucose production [31]. Obesity,as a crucial factor for inducing T2DM, may damage the epidermal growth factor domain-specific O-linked GlcNAc transferase (EOGT)-adropin axis, thus leading to a drop in adropin level, and in turn inducing or aggravating gestational T2DM, while the low level of adropin in breast milk is detrimental to the healthy development of the newborn [32,33]. Among the test population, the level of adropin is determined to be 5.8 ng/mL as the optimal threshold for distinguishing T2DM and non-T2DM with the sensitivity up to 81.9%, indicating that adropin may play an important role in the pathogenesis and evaluation of T2DM [25]. However, the application of adropin to distinguish T2DM must also fully consider the impact of gender and age, because the level of adropin in healthy men is higher than that of women,and its concentration also decreases as the aging progression [34,35].Previous studies have found that the level of NO in diabetic patients is generally lower than that in healthy people [36]. NO can increase lipid oxidation in surrounding tissues including skeletal muscle, liver and adipose tissues, promote transportation capacity of insulin and glucose to peripheral tissues such as skeletal muscle, and regulate gluconeogenesis, thus contributing to the regulation of obesity and insulin resistance, but the excessive nutrient consumption or HFD feeding will lead to the deficiency of NO [14,37]. Similarly, adropin can effectively inhibit the secretion of in flammatory factors, increase the expression of endothelial nitric oxide synthase (eNOS), reduce insulin resistance, and promote glucose and lipid metabolism, which plays a pivotal role in the prevention and intervention of obesity and T2DM as well as its complications [38-41]. Other researchers have injected adropin in diabetic rats to significantly reduce blood glucose,increase insulin secretion, improve mRNA expression of inducible nitric oxide synthase (iNOS), mitigate dyslipidemia, and suppress the secretion of TNF-α and IL-6 in pancreatic tissue (Fig. 1) [42]. In addition, all C57BL/6J mice with the knockout of ADROPIN gene after 30 weeks HFD feeding reveal glucose intolerance and eventually develop into T2DM [43]. However, the overexpression of transgenic ADROPIN gene improves glucose clearance, reduces fasting insulin,and rescues fatty liver phenotype of HFD-induced obesity mice [9].Adropin can up-regulate glucose transporters on the cell surface by increasing the phosphorylation of Akt, increase up-taking capacity of glucose, improve the sensitivity of insulin signal pathways, enhance the role of insulin, and promote metabolic flexibility of glucose utilization, so as to alleviate T2DM to a certain extent. Although the literatures have not described the major mechanism of adropin in alleviating T2DM, adropin has certain therapeutic and relieving effects on insulin resistance, T2DM, and lipid metabolic disorders through regulating adipocyte differentiation, glucose consumption,inflammatory factors and hepatic glucose secretion upon GPR19 mediation (Fig. 2).

Fig. 2 The role of adropin in obesity and T2DM. Adropin relieves obesity by promoting glucose consumption and inhibiting the differentiation of adipocytes to reduce the formation of fat and mitigate the progression of obesity. At the same time, it can reduce the level of in flammatory factors and inhibit glucose secretion in liver from relieving the progression of T2DM; it also reveals an inhibitory effect in obesity-induced insulin resistance; therefore, adropin has potential effects on the prevention and treatment of obesity and diabetes.

6. Adropin and diabetic complications

6.1 Diabetic nephropathy

The pathogenesis of diabetic nephropathy is complicated, and hyperglycemia is recognized as the major inducer, and approximately 30% of diabetic patients have renal complications as the major cause of death in people with diabetes [44]. Currently, clinical treatment only can alleviate the symptoms of diabetic nephropathy and delay the progression of end-stage renal disease, but cannot reverse end-stage renal disease. Trace albuminuria has traditionally been used as the leading diagnostic marker of early-stage microvascular complications that often lead to end-stage renal disease [44]. However, under the high glucose environment, diabetic nephropathy also can active NF-κB to induce the expression of IL-1β, IL-6, IL-18 and TNF-α,thus promoting the aggregation of type IV collagen, laminin and fibronectin, and leading to renal damage, fibrosis and renal failure eventually [45,46]. Previous studies have confirmed that adropin is also expressed in renal tissue, and after excluding the influence of gender and age, the level of adropin is negatively correlated with the occurrence of diabetic nephropathy [47,48]. The decreased secretion of adropin in both diabetic rats and ADROPIN knockout mice could stimulate an increasing trend in the expression of TNF-α, IL-6 and other inflammatory factors and the reduced phosphorylation level of eNOS. With the increase in generation and secretion of adropin,it reveals an obvious effect on promoting the production of NO and up-regulation of vascular endothelial growth receptors (VEGFR).Therefore, adropin may prevent endothelial cells from alleviating diabetic nephropathy by promoting anti-inflammatory factors and NO production [43] (Fig. 3). Similarly, the factors associated with the generation and secretion of adropin play a vital role in the pathophysiological development of diabetic nephropathy.

6.2 Diabetic retinopathy (DR)

DR is a common complication during the course of diabetes mellitus, and can be divided into proliferative diabetic retinopathy(PDR) and non-proliferative diabetic retinopathy (NPDR) according to retina with or without generation of new blood vessels. The patients with type 1 diabetes mellitus (T1DM) and nearly 60% of T2DM patients with diabetes history over 20 years have retinopathy [49].Among these patients, microvascular disease, inflammation, and neurodegeneration are the major causes of diabetic retinopathy [50].Hyperglycemia causes the production of advanced glycation end products (AGEs), and can change the structure and function of vascular endothelial cells, when AGE receptors lead to the transcription of vascular endothelial growth factor (VEGF) and pro-in flammatory cytokines such as TNF-α, IL-6 and IL-1β. Previous studies have also shown that TNF-α is correlated with diabetic retinopathy, and can cause disordered function of vascular endothelial cells in the end [51,52]. At the same time, the increased oxidative stress also can damage the function of normal cells and induce in flammation, thus resulting in neurodegenerative change and diabetic retinopathy [53,54]. Compared with T2DM patients without DR and healthy subjects, serum and vitreous adropin concentrations in T2DM patients with NPDR and PDR are decreased successively, indicating that the level of adropin may be negatively correlated with the severity of diabetic retinopathy. Simultaneously, studies have shown that adropin can effectively inhibit inflammatory responses caused by monocytes/macrophages in vascular endothelial cells and promote the proliferation of vascular smooth muscle, and reduce apoptosis induced by TNF-α to improve the quality of blood vessels [55].Although the concentration of adropin in serum and vitreous have been found to be associated with the risk of T2DM and diabetic retinopathy, the specific mechanisms are still unclear, which may be due to the anti-in flammatory and endothelial protection effect during the development of diabetic retinopathy [56].

6.3 Diabetic vascular diseases

When blood vessels are at a high blood glucose environment for a long time, the vascular endothelial damage and lesions such as diabetic foot and cerebrovascular accidents could take place [57].Endoplasmic reticulum (ER) stress of endothelial cells may be an important factor in vascular endothelial injury in T2DM. Human aortic endothelial cells at high glucose and high fat environment can up-regulate the expression of inflammatory factors such as monocyte chemoattractant protein 1 (MCP-1), vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1),and inflammatory factors such as TNF-α, IL-1β, and IL-6 [58].Meanwhile, the incidence of ischemic stroke will increase and is not conducive to subsequent clinical recovery, while adropin can achieve a certain neuroprotective effect by reducing the markers of oxidative damage [40]. However, the low level of adropin is found to be closely associated with endothelial dysfunction in patients with T2DM, and adropin and HbA1c are independent risk factors for T2DM endothelial dysfunction [59,60]. In in vitro and in vivo injury models, adropintreated endothelial cells exhibit more pronounced cell proliferation,migration, capillary formation and reduced capillary permeability, and the suppressed TNF-α-induced apoptosis [61]. In addition, adropin can up-regulate the phosphorylation of Akt at the site of Ser473 and eNOS at the site of Ser1177 through VEGFR2-PI3K-Akt and VEGFR2-ERK1/2 signal pathways to increase the phosphorylated endothelial nitric oxide synthase (p-eNOS)/eNOS ratio in skeletal muscle and increase the generation of vascular NO and bioavailability of NO to protect blood vessels and indirectly increase the utilization of glucose [55,61,62]. Adropin also can modulate the permeability of vascular endothelial cells under the hypoxic environment by inhibiting Rho-associated kinase (ROCK) - myosin light chain 2(MLC2) signal pathway [63] (Fig. 3). Therefore, adropin also plays an important protective role in cardiovascular endothelial function not only in diabetic patients but also in obese adolescents and the elderly patients with atherosclerosis [7,64]. The protective effect of adropin on the cardiovascular system may be achieved by increasing insulin sensitivity, anti-in flammatory effect and NO level.

6.4 Diabetic cardiovascular disease

Diabetic cardiovascular disease is one of the critical complications, and increasing glucose utilization in the myocardium has been proposed to reverse cardiomyopathy in obese and diabetic patients. As reported in previous studies, continuous injection of adropin in the peritoneal cavity of mice with long-term HFD could result in the significant oxidation of blood glucose, indicating that adropin can increase glucose oxidation under the condition with heart failure and may provide a future treatment strategy for diabetic cardiomyopathy [65,66]. Acute injection of adropin in mice also can promote the activation of the downstream pathway of cardiac insulin [66],and regulate the expression of mitochondrial acetyltransferase GCN5L1 [65], thereby improving glucose uptake and consumption by cardiomyocytes accompanying higher cardiovascular function.In T2DM patients combined with coronary heart disease, the level of adropin in serum is significantly lower than that in patients with coronary heart disease alone, and the reduction of adropin level maybe increase the risk of coronary atherosclerosis, but it may be due to the reduced insulin resistance or dysfunctional secretion of NO, which further suggests that the level of adropin is negatively correlated with the severity of coronary artery disease [67]. At the same time, heart tissue also can secret adropin, so the level of adropin in serum of patients with coronary heart disease can be used as a potential biomarker to re flect the status of cardiac damage and necrosis,even has a certain correlation with atrial fibrillation and atrial remodeling [68,69]. Therefore, in patients with diabetic cardiovascular diseases, adropin may play a certain therapeutic and mitigating role through improving glycolipid metabolism and increasing NO release (Fig. 3).

Fig. 3 Molecular mechanisms of adropin in the prevention and treatment of T2DM and its complications. Obesity and T2DM reduce the secretion of adropin in the body, while adropin activates Akt by promoting the secretion of insulin and vascular endothelial growth factor receptors, and controlling blood glucose and improving diabetic complications by the generation of NO. The complications of T2DM include diabetic nephropathy, diabetic retinopathy,diabetic cardiovascular or vascular disease, and the anti-in flammatory effects of adropin are effective in relieving these diseases.

6.5 Diabetic encephalopathy

During the development of diabetes, a series of lesions also appear in the nervous system, which called diabetic encephalopathy. With the prolongation of the survival time of diabetic patients, diabetic encephalopathy also become an important potential complication,mainly manifesting as cognitive decline, brain atrophy, and abnormal changes in the morphology and function of blood vessels, neuron and glial cells [70]. Although the direct mechanism of action of adropin in diabetic encephalopathy has not yet been specifically confirmed,studies have found that there are certain positive effects in aginginduced neurological decline and Alzheimer’s disease, such as promoting nerve regeneration, improving neuron energy metabolism,inhibit in flammation, and ultimately improving learning and memory function [71,72]. After 6-day intracerebroventricular adropin injection in 3-month-old rats, the rats showed better memory in Morris water maze, Y-maze and object location recognition (OLR) tests, which may be related to the activation of Akt/CREB/BDNF signal pathway by adropin [73]. In addition, adropin can also regulate paraventricular nucleus (PVN) to affect water intake [74]. As the research can be seen that adropin can directly participate in the regulation of the function of the central nervous system, and further understanding of the role of adropin in diabetic encephalopathy may provide new therapeutic approaches for diabetes-induced central nervous system diseases.

7. The strategies to promote the secretion of adropin

7.1 Exercise promotes the secretion of adropin

Aerobic exercise can effectively improve various functions in the body and induce the secretion of adropin. Even after moderate exercise training in an elderly group with limited mobility, the level of adropin is significantly higher than that in the sedentary group [7].Exercise training has a certain effect in changing adropin level and vascular reactive hyperemia index in obese people, which is also correlated with improving training efficiency of atherosclerosis and obese people [64,75]. On the other hand, regular exercise can improve glycemic control and insulin secretion in diabetic patients,thus effectively increasing insulin sensitivity, activating metabolic enzymes to reduce fat synthesis, and enhancing the consumption of adipose tissue to improve mitochondrial function via reduced nicotinamide adenine dinucleotide (NAD+)/NADH and increased coenzyme A (CoA)/acetyl-CoA (acetyl-CoA) ratio [36,76,77]. In addition, previous studies have also shown that high-intensity interval training (HIIT) has a better effect in promoting adropin secretion than continuous exercise training [78]. However, these limited studies have shown that adropin levels seem to be related to rapid fat-reducing exercise training. Therefore, exercise can be used as an interventional strategy to effectively stimulate the secretion of adropin, thereby significantly alleviating the symptoms associated with T2DM.

7.2 Functional foods promote the secretion of adropin

The secretion of adropin is mostly affected by diets, and some functional foods also play an important regulatory role in the generation and secretion of adropin, which provides a new way for dietary intervention in the secretion of adropin. For example,myricetin can significantly increase the secretion level of adropin [79].Moreover, fructose as a monosaccharide, short-term fructose intake can increase the circulating concentration of adropin. Although current studies have shown that the intake of fructose has less effect on blood glucose, excessive intake can also lead to an increased risk of cardiovascular diseases, metabolic diseases and high triglycerides in blood. Therefore, appropriate intake of fructose is particularly critical, because adropin level is negatively correlated with the intake of high fat diet, and excessive fructose can be easily converted into accumulated fat [6,80]. As us well known, fish oil is rich in n-3 unsaturated fatty acids, and has protective effects on cardiovascular diseases. At the same time, fish oil can also effectively increase the secretion of adropin so that the daily diet has the necessity for appropriate intake of foods or supplements enriched unsaturated fatty acids or fish oil. Similarly, probiotics have shown the potential to promote the secretion of adropin. For example, in a clinical trial of overweight and obese subjects, adropin level in the probiotic group reveals an obvious increase [81]. In daily life, the appropriate increase in the consumption of fructose, unsaturated fatty acids including deepsea fish, and probiotics will effectively promote the generation and secretion of adropin to prevent or rescue these metabolic diseases.

7.3 Drugs and surgeries promote the secretion of adropin

Surgery and drug are two major interventions in diseases, and they also seem to play a positive role in promoting the secretion of adropin,which may change the internal environment of the body to reduce the inhibition of adropin or directly promote the secretion of adropin.Doxorubicin, a widely used anti-cancer drug can increase adropin level in heart and serum of rats when injected intraperitoneally [82].In the cell culture of human umbilical endothelial cells and rat smooth muscle with atorvastatin, the concentration of adropin protein and its mRNA is increased [83]. Valsartan combined with amlodipine used in hypertension patients with obesity can stimulate the obvious generation and secretion of adropin [84]. The level of adropin reveals the obvious change accordingly after surgery for some diseases, for example, the increased secretion of adropin may be accompanied with the decreased inflammatory factors after adenotonsillectomy in children with obstructive sleep apnea [85]. In the same way, after bariatric surgery, the secretion of adropin, preptin and irisin is also increased [86,87]. Although relevant drugs and surgeries have a positive effect on the secretion of adropin, the specific mechanisms of these drugs are still unknown. These studies will provide us with a novel reference for the development of useful intervention methods.

7.4 Normal biological rhythm promotes the secretion of adropin

Biological rhythm also has a certain correlation with the secretion of adropin no matter in animals or human. A series of experiments have confirmed that the secretion of adropin could be induced during food digestion at its peak time at night, which may be regulated by retinoic acid receptor-related orphan nuclear receptor α/γ (RORα/γ),as evidenced by the studies in rhesus monkeys with increased adropin secretion and coincidence with feeding time [88]. However,recent studies have found the peak of adropin is consistent with the transcriptional activation of RORα/γ, especially in liver, with the synchronous increase of adropin and RORα after HFD stimulation,while the lowest level of secreted adropin is highly correlated with Reverb transcription [88,89]. In addition, the expression of ENHO gene could be affected through regulating Reverb inhibitor activity and RORα/γ transcriptional activation by small molecules such as Reverb agonist SR9009 [88]. However, current studies on biological rhythm and adropin are extremely limited, and the functional regulation of biological rhythm should be further explored to elucidate its correlation with the secretion of adropin and underlying regulatory mechanisms.

8. Future perspectives

Adropin has very limited studies on its functions and clinical trials since its discovery in 2008. Currently, the detected changes in adropin levels in patients with metabolic diseases and adropin gene knockout mice have confirmed a close correlation with obesity, T2DM and their complications so that adropin may be the potential target for the prevention and targeted treatment of obesity, T2DM, and their complications. In addition, external factors also show a regulatory effect on adropin levels, such as exercise, dietary supplements, drugs,and biological rhythm regulation (Fig. 4). It also suggests that adropin can also be used as a potential functional food supplement or drug to prevent and treat related metabolic diseases. Unfortunately, although adropin has gained extensive attention and exploration, its specific signal pathways and potential mechanisms in these metabolic diseases are still unclear. Therefore, future mechanistic explorations of adropin need to be further conducted from following various angles such as the correlation between adropin and autophagic signal pathways and microRNA-mediated adropin regulation, and specific delivery style or formulation for targeted administration.

Fig. 4 Potential strategies to promote the secretion of adropin. Aerobic exercise, biological rhythm, unsaturated fatty acids, probiotics and fructose have a potential effect on promoting the secretion of adropin.

Con flict of interest

The authors state that there is no con flict of interest.

Acknowledgements

This work isfinancially supported by the National Natural Science Foundation of China (No. 31771318), Hubei Superior Discipline Groups of Physical Education and Health Promotion, and the 14thFive-Year-Plan Advantageous and Characteristic Disciplines (Groups)of Colleges and Universities in Hubei Province for Exercise and Brain Science, as well as Chutian Scholar Program and Innovative Start-Up Foundation from Wuhan Sports University to Ning Chen.