Adropin as A Fat-Burning Hormone: History
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Subjects: Agriculture, Dairy & Animal Science
Contributor:
Marek Skrzypski

Adropin is a unique hormone encoded by the energy homeostasis-associated (Enho) gene. Adropin is produced in the liver and brain, and also in peripheral tissues such as in the heart and gastrointestinal tract. Furthermore, adropin is present in the circulatory system. A decade after its discovery, there is evidence that adropin may contribute to body weight regulation, glucose and lipid homeostasis, and cardiovascular system functions.

  • adropin
  • Enho
  • adiposity
  • metabolism
  • type 2 diabetes
  • liver
  • cancer
  • cardiovascular system

1. Discovery of Adropin and the Adropin Receptor

In 2008, Kumar et al. identified a new hormone called adropin [1]. The authors of this pioneer work studied expression of genes in C57BL/6J (B6) melanocortin-3 receptor-deficient (Mc3r−/−) mice, which allowed for identification of an unknown liver transcript downregulated in obesity. Using bioinformatics and molecular biology it was found that this transcript encodes a secreted protein that was termed adropin (this name originated from Latin “aduro” which means “to set fire to” and “pinquis” which means “fats or oils” [1]). Secreted adropin protein is composed of 43 amino acids, and is produced by proteolytic cleavage of 76 amino acid precursors. Notably, the amino acid sequence of adropin is highly conserved among the species and is identical in rat, mouse, human, and pig [1]. Unfortunately, the plasma half-life of adropin is still unknown and remains to be determined.

2. Regulation of Enho mRNA Expression

As mentioned above, obesity caused by melanocortin receptor or leptin deficiency leads to reduced Enho mRNA expression in the liver [1]. Interestingly, caloric restriction in melanocortin receptor-deficient mice normalized Enho mRNA expression in the liver. Furthermore, Enho mRNA expression is affected by the composition of diet. Mice fed a high-fat diet (60% kJ from fat) for 3 months had reduced Enho mRNA in the liver as compared with lean controls [1]. Suppression of hepatic mRNA expression was also reported in Enho mice fed a high-fat diet for 31 days [2]. In contrast, exposure to a high-fat diet for 2 days resulted in an increase of hepatic Enho mRNA expression. A similar effect was observed after 28 days of feeding with a high-fat diet. Moreover, Enho mRNA expression in the liver is downregulated after 10 days of fasting [1]. To further elucidate the mechanism by which Enho mRNA expression is upregulated by diet enriched in fat, Kumar et al. studied the potential role of intracellular lipid sensors in this process. Surprisingly, in hepatocarcinoma HepG2 cells’ Enho mRNA expression was downregulated in response to treatment with different nuclear liver X receptor (LXR) agonists (GW3965 or TO9). Of note, LXR controls cholesterol and triglyceride metabolism. Contribution of LXRα in downregulation of Enho mRNA expression was confirmed in vivo. In mice, treatment with LXRα agonist GW3965 was accompanied by reduction of Enho mRNA expression in the liver [1]. Thus, rapid upregulation of Enho mRNA expression by lipids is not mediated via LXR activation. However, a recent work evaluating the rhythmicity of Enho mRNA expression [2] found that Enho mRNA expression is mediated via the nuclear receptors RORα and RORγ. Noteworthy, the same study showed that liver Enho mRNA expression is downregulated by cholesterol in vitro [2]. It is worth noting that an in vivo study showed that the expression pattern of Enho displays rhythmicity [3]. A recent study found that in the liver and majority of central and peripheral tissues in Rhesus macaques, Enho mRNA is mainly expressed during the day time [3]. In summary, these results indicate that Enho mRNA is downregulated by fasting, while its modulation by a high-fat diet appears to be biphasic. Short exposure to a diet enriched in fat (up to 1 month) causes stimulation of liver Enho mRNA while hepatic Enho mRNA decreases in animals challenged with a high fat diet for 2 months.

3. Modulation of Adropin by Body Mass Index (BMI), Diet, and Diabetes

Several studies consistently shown that adropin levels in serum are affected by diet and depend upon metabolic diseases. Serum adropin levels are upregulated in mice fed a high-fat diet for 48 h [4]. In contrast, in mice with high-fat diet-induced obesity, serum adropin levels are low (<1 ng/mL). An inverse correlation of adropin levels and body mass index (BMI) was also confirmed by human studies [5][6][7][8][9][10][11], suggesting that a low level of adropin is a hallmark of obesity. Nevertheless, a recent detailed study showed that this association should be interpreted cautiously. For example, it was shown that in young lean men adropin levels are increased [2]. However, the same study showed that increased circulating levels of adropin is a risk factor for obesity in the middle and late stages of life [2]. In addition, serum adropin levels are also affected by sex. For example, women have lower circulating adropin levels as compared to men [5]. Furthermore, it was shown that in men, but not in women, circulating adropin is negatively associated with low-density lipoprotein (LDL) cholesterol levels [2].
This is in line with the results of in vivo and in vitro studies that showed that cholesterol suppresses Enho mRNA expression leading to lower adropin production. However, adropin overexpressing mice are not protected from hypercholesterolemia and atherosclerosis [2]. Therefore, adropin is not involved in cholesterol uptake from nutrition or cholesterol biosynthesis. In addition to lipids, it was shown that circulating adropin levels can be affected by carbohydrates intake. For example, a fall of adropin in serum was detected in mice fed a high-carbohydrate diet [4]. Interestingly, it was shown that glucose consumption suppresses adropin levels in circulation while fructose supplementation has an opposite effect [12]. Importantly, stimulation of adropin by fructose was more pronounced in humans with higher triacylglycerol levels, suggesting a role of lipids in regulating circulating adropin. Recently, it was shown that low levels of circulating adropin can be used as a predictor of body weight gain and metabolic dysregulation in Rhesus macaques challenged with a high sugar (fructose) diet [3]. Animals with low adropin levels had higher fasting glucose as well as leptin levels in response to a fructose challenge. Additionally, the same study showed an inverse correlation between serum adropin levels and apolipoprotein C3 in animals fed a high-fructose diet [3]. It is worth noting that high levels of apolipoprotein C3 are positively correlated with plasma triacylglycerol [13]. Consistently, increased levels of apolipoprotein C3 in animals with low levels of adropin, which were fed a high-fructose diet, were accompanied by more severe hyperglycemia [3].
There is growing evidence demonstrating that circulating adropin levels depend upon diet preferences. It was shown that in women but not in men, serum adropin concentration positively correlated with fat intake [14]. In addition, humans with low adropin levels consume more carbohydrates (simple and complex carbohydrates) [15]. Nevertheless, it is unknown whether diet affects adropin levels or whether adropin influences nutritional habits. Therefore, an association of adropin with diet preferences needs to be discussed cautiously.
In summary, adropin levels are affected by body weight, diet composition, and various diet preferences. Importantly, low levels of adropin are predictors of body weight gain in animals challenged with a fructose-enriched diet.
There is evidence indicating that adropin levels can be affected by diabetes. Serum levels of adropin are lower in type 2 diabetic patients as compared to healthy controls [16]. In addition, low levels of adropin in type 2 diabetes mellitus are a risk factor for endothelial dysfunction [17]. Downregulation of adropin in circulation in type 2 diabetes was also reported by Chen et al. [18]. These patients, who also have fatty pancreases, have lower serum levels of adropin [18]. It is also important to note that patients with lower adropin levels show a Cys56Trp mutation in the Enho gene [18]. Lower levels of adropin in circulation was also reported in women with gestational diabetes [19][20]. By contrast, serum levels of adropin in type 2 diabetic patients were high [21]. Aydin et al. studied the effects of type 1 diabetes induction on adropin levels in rats. This study found that STZ-treated type 1 diabetic rats have higher adropin levels in serum compared with that of the control group [22]. Moreover, this study demonstrated that adropin concentration was increased in pancreas, liver, kidney, brain, and cerebellum. Similarly, another study showed increased levels of adropin in kidneys and muscles in type 1 diabetic rats [23]. In contrast, a recent work found that adropin levels are downregulated in children who suffer from type 1 diabetes [24]. Therefore, studies testing the concentration of adropin in both types of diabetes provided partially contradictory data. It cannot be excluded that species differences (rats vs. humans), progress of disease, and age of patients (children vs. adults) could account to these differences.
Furthermore, similar to Enho mRNA expression, circulating adropin levels are affected by diet composition. Glucose suppresses serum adropin levels, while fructose has the opposite effect. Nevertheless, the mechanism by which glucose and fructose differently modulate adropin levels remains to be investigated.

4. The Role of Adropin in Controlling Adiposity and Lipid and Glucose Metabolism

Studies on genetically engineered animals provided strong evidence indicating that adropin contributes to the modulation of adiposity and metabolism of glucolipids. It was found that adropin-overexpressing mice are protected from body weight gain when fed a high-fat diet for 6 or 8 weeks [1]. Of note, attenuation of body weight gain was accompanied by reduction of fat mass. On the other hand, the same study showed that adropin-overexpressing transgenic mice (Adr-Tg) challenged with a high-fat diet for 3 months had similar body weight as compared to wild type animals. These results suggest that adropin overexpression delays but not completely prevents diet-induced body weight gain. Moreover, it was found that Adr-Tg mice (male and female) fed a high-fat diet have lower fasting levels of insulin and triglyceride. In contrast, blood glucose levels were not affected by adropin. In addition, the same study showed that adropin overexpression is associated with reduced insulin resistance (the homeostatic model assessment of insulin resistance—HOMA-IR) and improved glucose tolerance [1]. Overall, these results provide strong evidence that adropin overproduction improves insulin sensitivity and glucolipid metabolism in obesity. This statement is supported by the results of studies in animals treated with exogenous adropin. Kumar et al. found that obese mice treated with adropin eat less and lose body weight. In addition, less striking hyperinsulinemia as well as attenuated hepatic steatosis are hallmarks in these mice [1]. Moreover, adropin-treated mice have low expression of lipogenic genes in the liver. This relationship was confirmed in animals treated with adropin for two weeks [1]. In addition to the beneficial metabolic effects in diet-induced obesity, adropin reduces blood glucose level, improves insulin sensitivity, and suppresses inflammatory markers in a rat model of type 2 diabetes [25]. Overall, these results collectively show that adropin is able to attenuate metabolic abnormalities in obesity as well as type 2 diabetes.
To elucidate the effects of adropin on metabolism, several studies characterized the direct effects of adropin on glucose and lipid metabolism. Importantly, it was found that adropin may contribute to the modulation of glucose synthesis. Thapa et al. reported low levels of basal and insulin-induced glucose production in the liver of diet-induced obesity (DIO) mice treated with adropin (450 nmol/kg b.w.) for three days [26]. Contribution of adropin to the hepatic glucose metabolism was also reported by Gao et al. [27]. This elegant in vivo work demonstrated that in mice with diet-induced obesity, exogenous adropin causes an increase of IRS1, IRS2, and AKT phosphorylation suggesting that adropin increases hepatic insulin sensitivity [27]. The same study showed that adropin-treated mice have reduced endoplasmic reticulum stress and JNK activity in the liver. Supporting the results of a previous study, it was found that adropin suppresses glucose production in hepatocytes that are mediated of cAMP/PKA [27]. This signaling pathway plays a prominent role in promoting glucose synthesis in the liver.
Furthermore, adropin controls the metabolism of glucose and lipids in skeletal muscles. Animals lacking adropin have increased fatty acid oxidation in muscles [28]. In contrast, exogenous injection into animals or overexpression of adropin stimulates glucose oxidation and reduces lipid oxidation in muscles. This process is mediated via PGC-1α. These results suggest that adropin may improve energy homeostasis by promoting glucose utilization in skeletal muscles [28]. Similarly, an independent study confirmed that adropin promotes glucose utilization in muscles, which was associated with increased activity of pyruvate dehydrogenase, indicating that adropin enhances glycolysis [29]. Moreover, the same study showed that adropin is able to improve mitochondrial functions leading to attenuation of incomplete fatty acids oxidation in muscles in mice with diet-induced obesity [29].
An additional target organ of adropin is the white adipose tissue. In a mouse model of obesity, adropin treatment suppressed lipogenic genes expression in adipose tissue [1]. Further evidence indicating that adropin may contribute to preadipocytes and adipocytes functions was published by Stein et al. who found that adropin the activates GPR19 receptor in 3T3-L1 cells [30]. Of note, these cells are able to differentiate into adipocytes, thus are commonly used as a cell model for studding adipogenesis and mature adipocytes functions [31]. Similarly, adropin stimulated proliferation of 3T3-L1 cells and rat primary preadipocytes in our own study [32]. These effects are mediated via ERK1/2 and AKT dependent mechanisms. In contrast, adropin suppresses differentiation of these cells into mature adipocytes [32]. These results provide evidence that adropin modulates energy homeostasis by interacting with white adipocytes. Overall, these results showed that adropin improves insulin sensitivity and glucose and lipid metabolism in obesity. Furthermore, adropin is able to improve insulin sensitivity and reduce hyperglycemia in animal models of type 2 diabetes. The regulation of metabolism by adropin appears to be dependent upon an influence of hepatic glucose synthesis and enhanced hepatic glucose oxidation. Furthermore, adropin may contribute to energy homeostasis by affecting lipogenic genes expression in adipose tissue while suppressing adipogenesis. Nevertheless, more in vivo experiments are required to further confirm all these data.

This entry is adapted from the peer-reviewed paper 10.3390/molecules25030549

References

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