The receptor is an important molecule that provides physiological regulation within the human bod by binding with the ligand to transduce biological signals (9). Peptides can specifically recognize and bind to receptors on the cell surface, thus exerting the effects of agonists or inhibitors (9). For example, neuropeptide Y (NPY) is involved in the establishment of insulin resistance in adipose tissue via the long-term overexpression of NPY5 receptor in the paraventricular nucleus (43), while neuromedin S can bind to neuromedin U receptors (NMUR; NMUR1 and NMUR2) (38). It is well-known that leptin inhibits food intake and increases energy consumption by acting on receptors in the central nervous system to regulate the activity of appetite-related central neurons in the brain (44).

A protein is the final form of gene function. Some polypeptides can bind to proteins directly, which hinders the normal function of the protein (45). For example, the long non-coding (lnc)RNA HOXB-AS3 encodes a conserved 53 amino acid peptide (8). The HOXB-AS3 peptide, not lncRNA, suppresses colon cancer growth by binding to its protein competitively (8). A small number of polypeptides can also affect the conformation and folding of proteins by directly binding with target proteins. For example, Amyloid beta peptide of Alzheimer's disease directly binds to the target protein and affects its conformation, serving a pivotal role in the pathogenesis of Alzheimer's disease (46).

Some peptides can promote or inhibit the release of specific hormones. The gastric growth hormone releasing polypeptide (ghrelin) is a polypeptide composed of 28 amino acids (47). When ghrelin is combined with growth hormone secretagogue receptor, it can promote the secretion of growth hormone (GH) (47). In addition, several intestinal peptides have been indicated to induce gastric leptin release, leading to weight loss (48,49).

Peptides have the advantage of being stable, having a low molecular weight and high lipophilicity (9). In recent years, the area of peptidomics has rapidly developed, and the association between numerous polypeptides have been investigated with the occurrence and prevention of obesity and its related complications (50,51). Therefore, identifying novel polypeptide drugs, which could prevent and cure obesity would improve the regulatory network of adipocyte function and offer new possibilities for the treatment of obesity. A list of some classical peptides together with their targets, sources and functions are presented in Table II.

Leptin is a protein hormone that is secreted by adipose tissue (52). It has been widely hypothesized that after entering the blood circulation, it participates in the regulation of sugar, fat and energy metabolism (52). Early in 1997, Montague et al (53) demonstrated that leptin was a significant regulator of human energy balance via genetic evidence. Studies have revealed that leptin treatment can cause anorexia, physical activity increase, weight loss and lead to endocrine function and metabolic changes, which have a positive effect on the diet and nondigestive behaviors of patients with leptin deficiency (54,55). Leptin is primarily produced by adipose tissue, but the stomach also produces a small amount (56). Therefore, it was hypothesized that leptin may serve an important role in diet control by cooperating with other satiety peptides (49,57). Evidence indicates that gastric leptin can be released by a number of intestinal peptides such as ghrelin and cholecystokinin (49,56). In addition, it is known that insulin is a hormone released into the blood shortly following the ingestion of food, and can also stimulate the secretion of gastric leptin (58). In a previous study, insulin and leptin were indicated to increase WAT browning and energy consumption and prevent diet-induced obesity in combination, by activating hypothalamic neurons (59).

Over a period of time, there has been an increase in the amount of research investigating the role of leptin in the pathogenesis of obesity (60). However, recently, numerous studies have recognized that leptin may also participate in the adaptation to energy deficiency (61,62). Some studies have indicated that leptin participates in the regulation of neuroendocrine response to starvation, the change of hormone concentration and has an impact on the activity of the sympathetic nervous system and reproductive function (63,64).

NPY is a type of polypeptide molecule that widely exists in the central and peripheral nervous system, is a single-chain polypeptide and is composed of 36 amino acids (65). Injection of NPY into the hypothalamus has been revealed to induce appetite and regulate energy metabolism, and the expression level of NPY has previously been associated with leptin (66). Loh et al (67) demonstrated that knockout of NPY could alleviate obesity induced by leptin deficiency in mice. Previous studies have also revealed that NPY could not only antagonize the activity of the sympathetic nervous system, reduce the lipolysis of white adipocytes and inhibit the heat production of brown adipocytes (68), but could also directly act on NPY receptors in the peripheral adipose tissue to promote adipogenesis, leading to obesity (69). Furthermore, NPY is involved in the downstream mechanism of CREB phosphorylation by inhibiting cAMP accumulation and the cAMP-PKA-dependent p38 MAPK pathway (70). Wan et al (11) demonstrated that NPY reduces dibutyryl-cAMP activity of brown adipocytes by inhibiting brown fat-related gene expression and mitochondrial function.

GLP-1 is secreted by ileal endocrine cells and can promote insulin secretion (71). It has been successfully marketed as a drug to treat type 2 diabetes (71). In the treatment of obesity, it was previously found that GLP-1 and its receptor agonists could inhibit food intake, reduce weight and alleviate obesity (72). The GLP-1 receptor is widely expressed in the hypothalamus, particularly in the supraoptic nucleus, the paraventricular nucleus and the arcuate nucleus (72). GLP-1 acts on the GLP-1 receptor to inhibit food intake (73). In a previous study, it was demonstrated GLP-1 receptor-KO mice did not become obese (74). Injecting GLP-1 into the peripheral or central nervous system has also been indicated to effectively reduce the intake of food in rats (74). Furthermore, Perez-Tilve et al (75) indicated that GLP-1 increased energy consumption and increased body temperature in patients with obesity. In an in vitro experiment, GLP-1 stimulation on differentiated 3T3 cells and human adipocytes was demonstrated to inhibit gene expression associated with differentiation and promote gene expression associated with lipid degradation (76). In addition, GLP-1 receptor has also been revealed to promote browning of white fat through the SIRT-1-dependent pathway (77).

Ghrelin is a 28-amino-acid polypeptide that is secreted by X/A-like cells of the gastric acid secreting glands, and is also expressed in the small intestine and the hypothalamus (78). Ghrelin is an endogenous ligand of the GH secreting hormone receptor (GHS-R), and when bound to GHS-R, it can stimulate the secretion of GH (78). In a previous clinical study, it was indicated that ghrelin injection caused a hunger response and significantly increased food intake (79). This is consistent with the fact that ghrelin injection could also promote gastrointestinal motility, stimulate gastric acid secretion and protect gastric mucosa (80). Ghrelin primarily acts through the central appetite regulatory network, and it is also the first confirmed active appetite promoting factor (81). Tschöp et al (82) revealed that injection of ghrelin into the ventricle or periphery of the rat brain increased food intake, which was also consistent with the effect of NPY injection. In additional studies, injection of ghrelin into the central nervous system of NPY-KO rats was demonstrated to increase food intake, suggesting that the role of ghrelin in promoting food intake does not depend solely on NPY (83). Furthermore, in animal studies (84,85), it was also revealed that ghrelin could reduce energy metabolism, promote lipid accumulation in white adipocytes, inhibit BAT function and lead to obesity. Intervention of mature 3T3-L1 cells in vitro promotes the secretion of pro-inflammatory factors (86). In addition to the effect of dietary regulation on obesity, ghrelin also accelerates metabolism. The peripheral injection of ghrelin can reduce fat utilization in rodents and cause obesity, while the intracerebral injection can lead to food intake and weight gain (82). Notably, ghrelin has also been associated with sleep. Ghrelin increases within 1 h of sleep and regulates sleep-promoting GHs, which contribute to slow-wave sleep (87). Based on the multiple functions of ghrelin, ghrelin analogues, as stimulants and inhibitors, could be used as clinical drugs for the treatment of related diseases such as digestive and metabolic diseases, particularly in the treatment of obesity using ghrelin inhibitors (88).

AM2/intermediate is a secreted peptide, which serves a significant role in protecting the cardiovascular system (50,89). AM2 treatment has been demonstrated to significantly reduce blood glucose levels, improve glucose tolerance and insulin sensitivity by inhibiting major histocompatibility complex (MHC) II in adipocytes (90). Similarly, in a mouse model, the aAM2 transgenic mice showed more energy consumption due to their increased oxygen consumption and carbon dioxide production (12). These effects may be due to the decrease of PGC1α acetylation and the increase of AMP activated protein kinase phosphorylation, which lead to the interaction between PGC1α and PR domain containing 16, and the promotion of the uncoupling protein 1 (UCP1) expression in adipocytes (12,91). These results suggest that upregulation of UCP1 is a way for endogenous AM2 to participate in energy metabolism of adipocytes.

The irisin protein is encoded by the FNDC5 gene and is expressed in both human adipose tissue and muscle (92). A previous study demonstrated that irisin was associated with insulin resistance and obesity (93). The results indicated that the levels of circulating irisin and the expression level of the FNDC5 gene in adipose tissue and muscle were significantly lower in patients with obesity and type 2 diabetes compared with that in patients without these diseases, suggesting that the loss of brown-like characteristics may be a potential target for obesity treatment (93). Similarly, in a study by Pérez-Sotelo et al (94), using stable gene silencing of FNDC5, the results revealed that FNDC5-KO adipocytes exhibited reduced UCP1 expression levels and enhanced adipogenesis. In addition, a previous study revealed that FNDC5 and/or FGF21 treatment increased thermogenesis and upregulated brown fat gene expression, suggesting that exercise-induced irisin secretion may have evolved from muscle contraction associated with tremor, which in combination with FGF21, promotes brown fat thermogenesis (95). Irisin-mediated muscle-adipose crosstalk may represent a thermogenic, cold-activated endocrine axis, which could be used in the development of obesity therapeutics (95).

Adropin is a secreted peptide that is composed of 76 amino acids translated from the energy homeostasis associated gene, which has been associated with metabolic control and vascular function (96). Adropin does not directly regulate food intake; however, it has been indicated to be involved in the prevention of insulin resistance, dyslipidemia and impaired glucose tolerance, thus preventing obesity (97). In in vitro experiments using primary mouse hepatocytes, adropin 34-76 was demonstrated to directly affect liver metabolism, and reduce glucose production and PKA-mediated phosphorylation (51). Gao et al (51) indicated that the major hepatic signaling pathways contributed to the improved glycemic control achieved with adropin 34-76 treatment in cases of obesity. In addition, the function of adropin gene KO was investigated in C57BL/6J mice and the results revealed that adropin deficiency could aggravate the metabolic defects caused by a high-fat diet (HFD) (98). In cell experiments, adropin was found to reduce lipid accumulation, as well as the expression of proadipogenic genes in 3T3-L1 cells and rat preadipocytes, suggesting that adropin attenuates the differentiation of preadipocytes into mature fat cells (99). In summary, these results suggested that adropin serves an important role in fatty acid metabolism control, metabolic homeostasis, impaired glucose tolerance and protection from insulin resistance.

Preptin is a derivative of the proinsulin growth factor II and composed of 34 amino acids (100). It is secreted by pancreatic islet β cells and considered to be a physiological enhancer of insulin secretion (100). In addition, preptin can stimulate the proliferation, differentiation and survival of osteoblasts (101). In terms of metabolism, a previous study demonstrated that the primary function of preptin was to moderate glucose-mediated insulin release, which in return regulated the metabolism of carbohydrates, proteins and lipids (100). Consistent with this conclusion, another study revealed that preptin was significantly higher in patients who were obese and overweight compared with that in the control group, suggesting that the elevated serum preptin, together with insulin resistance are associated with obesity and overweight (102). In addition, a positive correlation was identified between the concentration of preptin and insulin resistance (102). However, the specific mechanisms governing this requires further investigation.

The core functional fragments of polypeptides are very short, usually only a few amino acids in length, and highly homologous fragments often have similar functions (103). GLP-1 has two bioactive forms in vivo; GLP-1 (7-37) and GLP-1 (7-36) amides. Among them, GLP-1 (7-36) amides are easily degraded by dipeptidyl peptidase IV (DPP IV) and neutral endopeptidase (NEP) 24.11 in the blood (104). GLP-1 (7-36) was indicated to be cleaved by DPP IV to produce GLP-1 (9-36), while GLP-1 (28-36) and GLP-1 (32-36) were produced by NEP 24.11(104). The role of GLP-1 (9-36) and GLP-1 (28-36) in promoting energy metabolism and inhibiting insulin resistance to prevent diabetes has been supported (105,106). Recent studies have indicated that 5-peptide GLP-1 (32-36) also serves a similar role (107). Short peptides are more likely to escape the degradation of proteases and may have improved functions compared with that in the original versions, which is also an important way to modify polypeptide drugs (103). GLP-1 and its homologous fragments serve similar roles. Esenatide, a novel compound with natural GLP-1 activity, has been approved for use in the treatment of type 2 diabetes (108). These results suggested that novel polypeptide drugs to treat obesity using homology could be identified.

Fragments of protein molecules were originally hypothesized to be non-functional peptide segments; however, recent studies have revealed that they have important functions (109,110). These can be secreted as hormone molecules into the extracellular space, transported to target organs and serve similar or opposite roles with protein precursors (109). Early studies on slit guidance ligand 2 (SLIT2) have focused on brain development. A previous study (111) has revealed that beige adipocytes could synthesize and secrete SLIT2, which is regulated by the PRDM16 gene. In vivo experiments and cell studies have also revealed that SLIT2 could promote adipose tissue heat production, enhance energy metabolism and regulate blood sugar levels (111,112). Further studies have indicated that the SLIT2 protein could be cleaved into fragments of different sizes, and the 50 kD fragment of the C-terminal end also has a similar function of the SLIT2 protein (111). The mechanism of action is primarily through the activation of the PKA signaling pathway. Furthermore, previous studies investigating neonatal progeroid syndrome (NPS) have demonstrated that NPS was associated with the truncated mutation in the FBN1 gene at the 3' end, which results in the inability of profibrillin to process fibrillin-1 and asprosin (the 25 kD peptide segment) (113). Asprosin has been indicated to be significantly elevated in the blood in individuals who are insulin-resistant and in mouse models, to bind to liver surface receptors and promote the rapid increase of blood sugar levels by activating the ‘G protein-cAMP-PKA’ signaling pathway (113).

Endogenous peptides are important regulators of a number of biological processes, including heredity, maturity, aging and death (35,36). Among them, breast milk contains a number of natural peptides with different biological activities (114). It can regulate the immune system, and exhibits antimicrobial, antioxidant properties and decrease the risk of obesity, atherogenesis, arterial hypertension and type 2 diabetes (114,115). A previous study demonstrated that Valine-Proline-Proline is a tripeptide derived from casein, is composed of three amino acids, which can improve insulin resistance in mice fed with a HFD, and alleviates inflammation by reducing the secretion of tumor necrosis factor-α and interleukin-1β (116). K-casein-derived glycogenous peptide has been indicated to inhibit the proliferation of adipocytes and reduce their lipid accumulation (117). By analyzing the differentially expressed polypeptides in the breast milk of macrosomia mothers, Cui et al (118) indicated that the polypeptide, casein 24 from β-casein in breast milk, exhibited a killing effect on common pathogenic bacteria in newborns, while k-casein 89 could inhibit the proliferation of human preadipocytes. These findings provide novel information that may be used in the prevention of obesity and reveal the important role of milk-derived peptides in this disease. Human bodily fluid contains a large number of endogenous polypeptides, most of which are also derived from degraded fragments of protein precursors (119). The study investigating milk-derived peptides further suggests that endogenous polypeptides in bodily fluids serve an important role in regulating obesity and other diseases and provides a novel method for the treatment of obesity and other diseases including atherogenesis, arterial hypertension and type 2 diabetes.

Intracellular peptides are small molecular peptides that are 2-21 amino acids in length and are produced by proteasome or proteasome hydrolysis (120). Traditionally, the majority of these peptides are degraded by cell aminopeptidases, and a few are transferred to the endoplasmic reticulum to participate in antigen presentation of MHC I (120,121). At present, >400 intracellular peptides (122-124) have been identified in mouse tissues and human cell lines, and typically serve a role in the regulation of signal transduction, mitochondrial stress, growth and development (125,126). Since adipocytes are the primary site of lipid deposition, and obesity and its related complications are associated with the increase of adipocyte volume and dysfunction (1), research has now focused on the role of endogenous endopeptides in adipose tissue. In 2012, Berti et al (127) revealed that intracellular peptides (diazepam binding inhibitor, LDBI and VGN) derived from adipose tissue in rats could be used to improve insulin-induced glucose intake and it was preliminarily demonstrated that endopeptides were involved in adipocyte insulin resistance. EPO-derived Helix B-surface peptide, which is a source of erythropoietin, was demonstrated to inhibit the differentiation of 3T3L1 cells and secretion of inflammatory factors, as well as improving obesity and insulin resistance induced by a HFD (128). Na/K-ATPase-derived breakdown-derived peptide was also indicated to inhibit adipocyte differentiation and oxidative stress, thus reducing obesity and insulin resistance induced by a HFD (129). As a novel component of adipocyte function regulation, intracellular peptides are expected to receive more attention in future studies.