Peptide hormones play a prominent role in controlling energy homeostasis and metabolism. They have been implicated in controlling appetite, the function of the gastrointestinal and cardiovascular systems, energy expenditure, and reproduction. Furthermore, there is growing evidence indicating that peptide hormones and their receptors contribute to energy homeostasis regulation by interacting with white and brown adipose tissue. In this article, we review and discuss the literature addressing the role of selected peptide hormones discovered in the 21st century (adropin, apelin, elabela, irisin, kisspeptin, MOTS-c, phoenixin, spexin, and neuropeptides B and W) in controlling white and brown adipogenesis. Furthermore, we elaborate how these hormones control adipose tissue functions in vitro and in vivo.
Over the last several years, the interest in the metabolism of adipose tissue and its physiological role has increased significantly. This seems to be due to two main causes. The first is the discovery of leptin (the first adipokine), which changed the perception of this tissue [1,2], and the second is the fact that the number of overweight and obese people has increased dramatically in the 20th century [3]. Moreover, the development of new techniques for searching for biologically active substances based on virtual models and in silico research allowed for the discovery and description of many new biologically active substances, including proteins and peptides [4]. In this short review, we provide information on the impact of several newly discovered fpeptides on the metabolism and function of adipose tissue (white adipose tissue (WAT); and brown adipose tissue (BAT) and adipocytes.
Adropin controls glucose and lipid metabolism [5,6]. In 2008, Kumar et al., through microarray screening, identified an adropin peptide composed of 76 amino acids and found that its secretory signal peptide sequence is encoded by residues 1–33 [6,7]. Synthetic adropin, contains residues 34–76. This isoform is biologically active [8]. This amino acid sequence is highly conserved among mammals and is identical in humans, horses, rats and mice [6]. Adropin is encoded by the energy homeostasis-associated gene (ENHO), which is located on chromosome 9 in humans and on chromosome 4 in mice [8,9]. An abundant Enho mRNA expression is detectable in many areas of the brain and in the liver [6]. Adropin mRNA expression in the liver depends upon the nutritional status [10]. For instance, hepatic Enho expression in mice increases during the short-term intake of a high-fat diet. However, chronic exposure to a high-fat diet leads to a reduction of hepatic Enho expression. On the other hand, the expression of Enho mRNA is also low after fasting [6]. In addition to its expression in peripheral tissues, such as the pancreas, kidney, and heart [11], adropin is also present in the circulation [11,12].
GPR19, a member of the orphan G protein-coupled receptors family, is considered as a candidate for an adropin receptor [13,14]. GPR19 is a transmembrane receptor widely distributed throughout the body, including the brain, spleen, kidney, heart, liver and lung [15]. However, it needs to be pointed out that the interaction of adropin with GPR19 has not yet been documented. Furthermore, there is evidence indicating that adropin is a brain membrane-bound protein which interacts with NB-3. This interaction contributes to the development of cerebellum, which appears to be mediated via Notch1-dependent signaling [16].
The majority of the studies showed that circulating adropin levels are negatively correlated with body mass index [17,18,19,20]. Moreover, it was found that genetically engineered Enho-/-mice are characterized by an increased adiposity and impaired insulin sensitivity [21]. By contrast, adropin overexpressing mice fed a high-fat diet display a delayed body weight gain, compared with wild-type animals [6]. These data suggest that adropin may be involved in controlling adipose tissue functions. Recently, we showed that the adropin precursor gene, Enho, and its receptor, Gpr19, are expressed in white and brown undifferentiated and differentiated rat preadipocytes [22,23]. Moreover, ENHO mRNA was detected in the adipose tissue in baboons (Papio anubis) [10]. However, expression of ENHO mRNA was significantly lower as compared to other tissues such as brain or liver. Of note, Enho mRNA was found in murine hormone-sensing luminal cells in mammary gland [24]. In response to low temperature (4 °C) Enho mRNA was up regulated [24].
Furthermore, we found that adropin stimulates white and brown preadipocyte proliferation. The stimulation of white and brown preadipocyte proliferation by adropin was mediated through ERK1/2 and AKT activation, respectively. In addition, we found that, in white rat primary preadipocytes or 3T3-L1 cells, adropin suppresses the expression of Ppar γ, Fabp4, and C/ebp β at the mRNA level and attenuates lipid accumulation [22]. Similarly, we found that adropin downregulates intracellular lipid levels and the expression of Ucp1, Ppar γ, and Pgc-1 α mRNA during the differentiation of rat brown preadipocytes [23]. Keeping in mind that the abovementioned genes are involved in white and brown adipogenesis [25], these results suggest that adropin suppresses the differentiation of white and brown preadipocytes into mature fat cells.
Unfortunately, very little is known about the role of adropin in mature adipocytes. Nevertheless, there is evidence suggesting that adropin may be involved in lipid metabolism. It was found that mice overexpressing adropin and exposed to a high-fat diet display a lower mRNA expression of genes involved in lipid synthesis, such as Ppar γ, Lpl, and Fas [6]. By contrast, the expression of genes involved in fat oxidation (Acrp30, Pgc1α and Cpt1a) was not affected in mice overexpressing adropin. Little is known about the role of adropin in regulating glucose metabolism in adipose tissue. However, it is worth to note that in mice with adropin deficiency, glucose uptake was similar to that observed in wild-type animals [21]. Nevertheless, more experiments are needed to elucidate the role of adropin in controlling lipid metabolism and fat tissue formation in vivo.
In summary, adropin deficiency may lead to adiposity. By contrast, administration or overexpression of adropin protects against body weight gain in animals fed a high-fat diet. In vitro, adropin promotes the proliferation of white and brown preadipocytes and suppresses their differentiation into mature adipocytes. A brief summary of the function of adropin on adipose tissue metabolism was provided in Figure 1.
APELIN (APLN) and ELABELA (ELA, Toddler, apela) are peptide hormones whose biological activity is regulated via the apelin receptor (APLNR, APJ) [26,27]. APLNR belongs to a class A (rhodopsin-like) of G protein-coupled receptors (GPCR) [26]. APLNR is widely distributed in mammals, in the central nervous system as well as in peripheral tissues [28,29]. Both agonists of APLNR—ELA and APLN—can modulate multiple intracellular signaling pathways, such as adenyl cyclase (AC) and PKA (protein kinase A) [30].
Despite the fact that these peptides are 15 years apart in terms of their discovery (APLN was discovered in 1998; ELA, in 2013), they still arouse the interest of scientists around the world [31,32].
The apelin gene in the human and mouse genomes is located on chromosome X and encodes a 77 amino acid prepropeptide, pre-pro-apelin [33]. As a result of the post-translational processing of this precursor peptide, Apelin-17, Apelin-13, and [Pyr1]-Apelin-13 (with a pyroglutamate substitution at the N terminus of Apelin-13) are formed. All of these isoforms are biologically active. Previous studies showed that apelin and the APJ receptor are widely expressed in all mammalian peripheral tissues, such as the stomach, heart, lung, skeletal muscle, etc., as well as in some regions of CNS, e.g., in the brain, including the extrahypothalamic structures, such as the piriform cortex, the nucleus of the lateral olfactory tract, the central grey matter, the pars compacta of the substantia nigra, the dorsal raphe nucleus, and the entorhinal cortex [33,34,35,36,37,38].
Apart from research addressing the role of apelin in regulating carbohydrate-lipid metabolism and food intake, the link between apelin and the regulation of adipocyte’s functions was reported soon (2 years) after apelin’s discovery [38,39,40,41,42]. The current knowledge regarding the role of apelin in the regulation of adipocytes is derived from in vitro and in vivo experiments. As mentioned above, in 2001, Tatemoto et al. investigated the effect of apelin on lowering blood pressure and showed that apelin is expressed in adipocytes in rats, which was also confirmed one year later by De Falco and coworkers in human fat tissue [34,38]. Since then, many functions of apelin in regulating fat cells have been described, and all of them confirm that this peptide is a potent regulator of the metabolism of this tissue. Most studies are concerned with the role of this peptide in obesity. Later research of Boucher et al. proved that apelin is upregulated by insulin and obesity and could be secreted by adipocytes [35]. After these findings, apelin has been considered as a new adipokine. Later research also showed that APLN expression is regulated by many factors, whose balance is disturbed during the occurrence of many diseases related to adipose tissue. One of them is TNF α. The research showed that APLN mRNA expression is increased in response to this factor in human and mouse adipose tissue [43]. Other research also showed that apelin mRNA is downregulated by glucocorticoids in 3T3-L1 adipocytes [44] and upregulated by hypoxia [45], eicosapentaenoic acid [46], inflammation (LPS) [47], and the transcriptional proliferator-activated receptor γ (PPAR γ) coactivator 1 α (PGC-1 α) [48]. Moreover, in 2011, it was found that a blockade of the renin–angiotensin system ameliorates apelin production in 3T3-L1 adipocytes [49]. Apart from the description of the influence of many different factors on the expression of apelin, many effects of this peptide on the functioning of adipocytes were also demonstrated. One of the basic processes in adipose tissue is lipolysis and lipogenesis. In 2011, Yue et al. showed that apelin increases lipolysis in 3T3-L1 cells via the activation of AMP-activated protein kinase and the Gq and Gi pathways. In this study, the authors also showed that apelin-knockout mice have an increased abdominal adiposity and higher circulating FFA levels, and apelin infusion abolished this effect [50]. These findings were confirmed by other research groups, which demonstrated that APLN inhibits adipogenesis (through MAPK kinase/ERK dependent pathways) and basal lipolysis (through basal the AMP kinase-dependent enhancement of perilipin expression), and acute/hormone-stimulated lipolysis decreases the perilipin phosphorylation in 3T3-L1 and rat primary isolated preadipocytes. Moreover, it was found that apelin stimulates glucose uptake via the PI3K/Akt pathway, thus improving insulin resistance in 3T3-L1 adipocytes [51,52]. On the other hand, ex vivo research performed on human isolated adipocytes did not prove the stimulating role of APLN in lipolysis but showed that APLN stimulates the glucose uptake in these cells, thus increasing AMPK phosphorylation [53]. In 2015, Than and coworkers, using primary rat and mouse brown preadipocytes isolated from interscapular BAT, as well as human preadipocytes, also proved that APLN enhances brown adipogenesis and the browning of white adipocytes via the PI3K/Akt and AMPK signaling pathways [54]. A brief summary of the function of apelin in adipose tissue metabolism was provided in Figure 2.
The function of this peptide in the context of adipose tissue metabolism is still largely unknown. However, based on the literature data and its effect on metabolic pathways, such as the regulation of the SIRT3-mediated inhibition of oxidative stress through Foxo3a deacetylation [55] or the negative association between blood glucose level and ELA, these are grounds to assume that APLN and ELA may also be involved in the metabolism of adipose tissue [56,57]. In summary, the literature data indicate that both APLN and ELA are potent regulators of adipose cell metabolism. However, the effect of ELA is still unclear, and future studies are required.
Irisin, a newly reported molecule, was firstly described in animals, and since then, it has been one of the peptides of increasing research popularity. As part of the adipomyokines class, it interacts with adipose tissue and muscle tissue. Irisin was firstly described by Bostrom in 2012 at Harvard University. During this research, irisin was shown to be a myokine that is up-regulated by exercise [58]. The precursor of irisin, the FNDC5 protein, is built of residues of 209 aa, consisting of an N-terminal signal sequence, a fibronectin-type III domain, an unidentified region, a transmembrane domain, and a C-terminal part. The release of irisin is connected to the cleavage of the extracellular part of the FNDC5 protein [59]. Later research also demonstrated that irisin is expressed and produced by human muscle cells [60]. For many years, the receptor through which irisin exhibits its biological activity remained unknown. However, in 2018 Kim et al. showed that the effects of irisin in bone and fat are mediated via α V integrin receptors. In addi
