Skip to main content
Applied Biological Chemistry
Download PDF

Regulation of appetite-related neuropeptides by herbal medicines: research using microarray and network pharmacology

Applied Biological Chemistry volume 66, Article number: 68 (2023) Cite this article

Abstract

Anorexia means loss of appetite and is a state whereby a desire to eat is either reduced or eliminated resulting in reducing or stopping food intake. Sipjeondaebo-tang (SDT) and Hyangsayukgunja-tang (HYT) are prescriptions known to have appetite-improving effects, but studies on their mechanisms and active components are insufficient. The hypothalamus is the center of appetite control, and various appetite control mechanisms are known. We used mouse hypothalamic neuronal GT1-7 cells as appetite control center cells and analyzed the difference in efficacy between SDT and HYT using microarray and network pharmacology. Microarray analysis showed that SDT and HYT affect the regulation of genes related to appetite control in the digestive tract and central nervous system. Using network pharmacology, we analyzed the differential expression of neuropeptide Y receptors, glucagon, corticotropin-releasing hormone receptors 1, and 5-hydroxytryptamine receptor 4 among the 17 anorexia-related genes selected from the comparative toxicogenomics database and also analyzed the active components that affect gene expression. In conclusion, the appetite-related genes contributed to anorexia control, and the difference in the action mechanism of the two complex prescriptions could be explained.

Introduction

Anorexia means loss of appetite and is a state whereby a desire to eat is reduced or eliminated resulting in reducing or stopping food intake [1]. Anorexia has various causes such as nausea, vomiting, side effects of medication, psychological factors, and aging [2, 3]. Appetite is the psychological desire to eat, associated with sensory experiences such as the sight and smell of food or cognitive, emotional, social situations, and cultural conventions. Appetite is regulated by interactions between peptide hormones in the digestive tract or adipose tissue and the hypothalamus [4]. The hypothalamus is the center of appetite control, and various appetite control mechanisms are known. The hypothalamus regulates short- and long-term dietary intake by synthesizing numerous anorectic and orexigenic neuropeptides. The function and structure of several hypothalamic peptides, including melanin-concentrating hormone (MCH), cocaine- and amphetamine-regulated transcript (CART), orexins, neuropeptide Y (NPY), melanocortins, and agouti-related peptide (AGRP) have been studied in rodent models. In addition, peripheral neuropeptides, including bombesin, amylin, peptide YY (PYY3-36), ghrelin, and cholecystokinin (CCK), govern essential gastrointestinal processes, such as absorption, secretion, and motility, offer feedback to the central nervous system on nutrition availability, and may help regulate food intake [5].

Sibjeondaebo-tang (SDT) and Hyangsayukgunja-tang (HYT) are commonly used prescriptions for anorexia but have different components. SDT is a frequently prescribed herbal medicine comprising 10 herbs (Astragali Radix, Panax ginseng radix, Atractylodes Rhizoma Alba, Poria sclerotium, Rehmanniae Radix, Angelicae Gigantis Radix, Paeonia Radix, Cnidii Rhizoma, Glycyrrhizae Radix et Rhizoma, and Cinnamomi Ramulus) in Korea, Japan, and China [6]. SDT is also called Shi-Quan-Da-Bu-Tang in China and Juzen-taiho-to in Japan. SDT is used to treat both qi and blood deficiency syndromes by balancing Yin and Yang, and is also widely used for treating chronic illnesses by restoring physiological function and improving immunity [7]. HYT (named as “Xiang Sha Liu Jun Zi Tang” in Chinese) has been used for various digestive disorders, such as gastric flatulence, anorexia, nausea, and vomiting. HYT is commercially available and comprises 14 herbs: Cyperi Rhizoma, Atractylodis Rhizoma Alba, Poria Sclerotium, Pinelliae Tuber, Citri Unshius Pericarpium, Amomi Fructus Rotundus, Magnoliae Cortex, Amomi Fructus, Ginseng Radix Alba, Aucklandiae Radix, Aipiniae Oxyphyllae Fructus, Glycyrrhizae Radix et Rhizoma, Zingiberis Rhizoma Crudus, and Zizyphi Fructus [8].

Herbal medicine preparations are widely used owing to their long history and safety. They are effective in treating complex syndrome-type diseases owing to the complex efficacy of their various components. However, these preparations have many drawbacks, such as non-specific and weak efficacy, resulting in efficacy evaluation difficulties. Therefore, microarray and bioinformatic methods should be used that would facilitate the analysis of complex herbal prescriptions. In this study, we used mouse hypothalamic neuronal GT1-7 cells as appetite-regulating cells and analyzed the differences in the related genes by SDT and HYT using microarray.

Methods

Preparation of herbal prescriptions

SDT and HYT were prepared from a chopped herbal mixture by Hanpoong Pharmaceutical Co., Ltd. (Jeonju, Korea) and the Korea Institute of Oriental Medicine, respectively. Briefly, the mixture was added to 125 mL of distilled water and decocted at 90–100℃ for 3 h. The extract was filtered through filter paper with a 5 μm pore size. The filtrate was concentrated using an evaporator, and the remaining mass was vacuum-dried to obtain a powder. The powder was dissolved in dimethyl sulfoxide (DMSO) for in vitro experiments.

Cell cultures and viability

GT1-7 cells were maintained in high-glucose Dulbecco’s modified Eagle’s medium (DMEM; Corning, Manassas, VA, USA) supplemented with 10% fetal bovine serum (FBS; Atlas Biologicals, Fort Collins, CO, USA) and 1% antibiotics (100 U/mL penicillin and 100 U/mL streptomycin; Gibco BRL, Carlsbad, MD, USA). The cells were seeded at a density of 2 × 104 cells/well on a 96-well plate. GT1-7 cells were incubated at 37 °C in a 5% CO2 humidified incubator. The cells were treated under various concentrations (25, 50, 100, and 200 µg/mL) for 24 h. Cell viability was measured using an EZ-cytox assay kit from DoGenBio (Seoul, Korea) at 450 nm using a microplate reader.

RNA extraction

GT1-7 cells were treated with 25 and 200 µg/mL SDT and HYT, respectively. After 24 h, total RNA was isolated using the RNeasy mini kit following the manufacturer’s protocol (Qiagen Inc., Valencia, CA, USA). Subsequently, the purity was quantified by measuring the 260/280 ratio between 1.8 and 2.1. In addition, the integrity number (RIN) was over 7.

Microarray data collection and analysis

Cell samples were collected and subjected to total RNA extraction for use in the Clariom™ S Assay platform for mice. Following the manufacturer’s instructions, the extracted total RNA was converted into cDNA using the GeneChip Whole Transcript (WT) Amplification kit. Subsequently, the sense cDNA was fragmented and biotin-labeled using terminal deoxynucleotidyl transferase (TdT), facilitated by the GeneChip WT Terminal labeling kit. Approximately, 5.5 µg of the biotin-labeled DNA target was hybridized to the Affymetrix GeneChip Array and maintained at a consistent temperature of 45 °C for 16 h. After hybridization, the arrays were processed through a wash-and-stain cycle on a GeneChip Fluidics Station 450, followed by scanning with a GCS3000 Scanner (Affymetrix). Probe cell intensity data were generated and converted into a CEL file via the Affymetrix® GeneChip Command Console® Software. Furthermore, the Affymetrix Power Tools and R 3.3.3 software facilitated data analysis, allowing comprehensive examination and interpretation of the microarray data.

Analysis of the association between microarray data and anorexia

To compile a list of genes perceived to be associated with anorexia, we gathered list of genes from the toxicogenomics database (CTD) [9], where genes are curated by their associations with diseases in terms of markers, mechanisms, or therapeutics. We analyzed the fold-change in anorexia-associated genes in the microarray compared with that in the control. Genes with an absolute fold-change value ≥ 1.5 were presumed to be differentially expressed genes (DEGs). To infer the compound causing changes in the expression of anorexia-associated genes, we reconstructed a prescription-herb-compound-target network focusing on anorexia-associated genes that were differentially expressed. To build the network, information about the herb-component relationship was obtained from TM-MC, and compound-target information was gathered from curations by Hwang et al. [10], which included data from ChEMBL [11], BindingDB [12], STITCH [13], Herbal Ingredients’ Targets Database [14], and the Traditional Chinese Medicine Integrated Database [15].

 Statistical analysis

The data were performed using the GraphPad software (GraphPad Prism 5, USA). The results were analyzed using one-way analysis of variance to determine differences between the treatment and control groups. All data are presented as mean ± standard error of the mean. Values of *p < 0.05 were statistically significant.

Results

Cell viability in GT1-7 cells

We first investigated cytotoxicity under varying concentrations (25, 50, 100, and 200 µg/mL) of SDT and HYT in the GT 1–7 cell line. As shown in Fig. 1, both samples showed no cellular toxicity, even at high concentrations. SDT showed viability in 100 ± 0.28, 100.50 ± 0.06, 100.34 ± 0.48, 100.45 ± 0.49, 100.17 ± 0.20% (25, 50, 100, and 200 µg/mL) and HYT in 100 ± 0.28, 98.04 ± 0.51, 99.55 ± 0.19, 99.94 ± 0.50, 100.56 ± 0.49%, 25, 50, 100, and 200 µg/mL, respectively. Therefore, 25 and 200 µg/mL concentrations were selected for further study (Fig. 1).

Fig. 1
figure 1

SDT and HYT cell viability in GT1-7 cells. The cells were treated with various SDT and HYT concentrations for 24 h. Cell viability was determined colorimetrically using EZ-Cytox assay at absorbance 450 nm. The data are expressed as the means ± SD (n = 3). *p < 0.05 compared to control group

Full size image

Enrichment analysis

We conducted a pathway enrichment analysis based on the KEGG pathway [16] for DEGs and found that DEGs in samples treated by ‘HYT’ or ‘SDT’ were related to multiple pathways associated with digestive systems (including pancreatic secretion) and appetite regulations from the central nervous system (including apelin signaling pathway), and olfactory and nasal infection (olfactory transduction and Staphylococcus aureus infection). More specifically, pancreatic secretion was associated with DEGs in the high-dose group treated with ‘HYT’ or ‘SDT’, while salivary secretion was associated with the high-dose ‘SDT’ group. Serotonergic synapses were associated with DEGs in both the low-and high-dose ‘SDT’ groups, and the apelin signaling pathway was associated with DEGs in the high-dose ‘SDT’ group. The top 20 terms were selected based on the high-dose ‘SDT’ group; however, notably this does not imply that ‘SDT’ was more effective over ‘HYT’ in regulating the digestive system or appetite-related CNS regulations (Table 1).

Table 1 Top 20 terms in enrichment analysis based on the high-dose ‘SDT’ and ‘HYT’ groups. Bolded terms indicate referred terms for the indication of SDT and HYT. Bolded p-values indicate significant relationship between the corresponding pathways and the drugs.
Full size table

Association with anorexia

We identified 17 anorexia-related genes, including Tnf, Il1b, Tac1, and Npy, from the CTD. Among them, tachykinin 1 (Tac1), Gcg, Crhr1, Crhr2, Htt4, and Ifna2 were differentially expressed in cell lines treated with ‘SDT’ or ‘HYT’. Specifically, Npy5r, Npy1r, and Npy6r, which were associated with Npy, showed increased expression in the low-dose ‘SDT’ group. While the expression of Tac1 decreased in the high-dose ‘SDT’ group, the expression of Crhr2 and Ifna2 increased. Il2ra, which was associated with Il2, tended to decrease in all the experimental groups. In the high-dose ‘HYT’ group, a decrease in the expression of Gcg and Crhr1, which was not substantial in the other groups, was observed (Table 2, Additional file 1: Fig. S1).

Table 2 Fold-change of anorexia-associated genes in ‘SDT’ and ‘HYT’ treated cell lines compared to the control. Bolded gene symbols and fold-change values indicate significant changes in gene expression (|fold-change| > 1.5). Inference scores represent the strength of the inferred association between anorexia and the gene in the CTD database
Full size table

Compound on anorexia-associated DEGs

To infer which components within the prescription caused changes in the expression of anorexia-related genes, we analyzed a prescription-herb-compound-target network focused on anorexia-associated DEGs. As a result, we found that linolenic acid, roemerine, falcarindiol, palmitic acid, glycine, retinal, beta-ionone, aporheine, adenosine, thymidine, or oleic acid were associated with Gcg, Npy5r, Npy1r, or Htr4 (Fig. 2 and Additional file 1: Table S1). Naphthalene that is a kind of polycyclic aromatic hydrocarbons and known as a toxic carcinogen was omitted from the analysis.

Fig. 2
figure 2

 A prescription-herb-compound-target network focused on anorexia-associated differently expressed genes. Pentagons, squares, triangles, and circles indicate prescriptions, herbs, compounds, and genes, respectively. Edges between nodes indicate associations between entries corresponding to the nodes

Full size image

Discussion

Herbal preparations are widely used owing to their long history of treating illnesses and safety. SDT has been reported in studies and clinical cases to improve symptoms of anorexia caused by cancer, liver toxicity, and hemodialysis [17,18,19,20]. HYT is a modified prescription that improves the efficacy of Yukgunja-tang (YT). YT, also called Rikkunshi-to in Japan, is a traditional prescription used to treat upper gastrointestinal symptoms, such as anorexia, nausea, dyspepsia, and gastroesophageal reflux [21,22,23]. HYT and YT have been used to improve the condition of patients with cancer [23,24,25] and Parkinson’s disease [26] having anorexia. SDT is known to promote gastrointestinal motility to improve symptoms of anorexia [27, 28], and YT also improves gastrointestinal motility and symptoms of anorexia by increasing the level of ghrelin in plasma [29]. Most studies on the improvement of anorexia symptoms using SDT and YT focused on gastrointestinal motility; however, the difference in the mechanism of action of these two herbal medicines remains unclear.

Although herbal preparations are effective in treating complex syndrome-type diseases owing to the complex efficacy of their various components, these preparations have many drawbacks, such as non-specific and weak efficacy, making efficacy evaluation difficult. Therefore, we attempted to detect appetite regulation related to multiple genes by SDT and HYT using microarrays. We also used network pharmacological analysis to identify genes involved in improving anorexia in mouse hypothalamic neuronal GT1-7 cells.

Anorexia is associated with several neurotransmitters and neuropeptides in the hypothalamic feeding center, in which corticotropin-releasing hormone (CRH), serotonin (5-Hydroxytryptamine (5HT)), and brain-derived neurotrophic factor play a pivotal role [30]. NPY neurons in the hypothalamic arcuate nucleus are crucial for feeding regulation. Expression and secretion of NPY in the hypothalamus increase during fasting [31], and injection of NPY potently stimulates food intake [32]. Glucagon has been known to be related to glucose metabolism that causes satiety in many studies [33,34,35]. The anorexic action of glucagon inhibits food intake by sensing blood glucagon levels in the hepatic portal vein [36]. In addition, patients with anorexia frequently have glucose intolerance [37]. TAC1 is related to TAC precursor 1, and a study comparing neural stem cells between anorexia nervosa patients and controls reported that differential TAC1 receptor expression and an aberrant tachykinin neuropeptide signaling pathway may underlie eating disorders [38]. Analysis of SDT- and HYT-treated samples confirmed that appetite control and digestive system genes are related to gene expression. In addition, SDT confirmed that the improvement of anorexia symptoms is related to the NPY hormone in the hypothalamus, as a result of gene expression analysis. In addition, HYT and SDT also improved anorexia symptoms by suppressing gene expression and reducing loss of appetite for internal material such as corticotropin-releasing hormone and serotonin. In addition, active components related to Gcg, Npy5r, Npy1r, or Htr4 genes are predicted to be linolenic acid, roemerine, falcarindiol, palmitic acid, glycine, retinal, beta-ionone, aporphine, adenosine, thymidine, and oleic acid. Among these compounds, palmitic acid and oleic acid have studied in relation to appetite regulation [39, 40].

In the enrichment analysis, it is found that the targets are associated with genes that would be related to the olfactory and nasal infection such as olfactory transduction and Staphylococcus aureus infection. A temporary or long-term loss of smell can be caused by respiratory infections such as COVID-19, the common cold, and flu that infect olfactory support cells or the lining of the nose and throat [41]. Also, the olfactory decline that often accompanies aging is believed to negatively affect eating pleasure, appetite, food intake, and subsequently nutritional status [42]. Indeed, the olfactory receptors are considered to play a role in regulating appetite and provide opportunity to enhance appetite-related traits, such as feed intake and weight gain [43]. There are possibilities that the drug would be promote the activity of olfactory system and indirectly affects the appetite.

In contrast, this study has a limitation of difficulties in understanding the complex neurophysiological mechanism aspects of appetite regulation by complex emotions such as fear and depression through the interaction of the hypothalamic nerve and the neural network. In addition, our microarray analysis was derived from cell-based and computational experiments, and we believe that the efficacy of these results must be demonstrated through animal experiments.

In conclusion, our experimental results confirmed SDT and HYT efficacies in improving anorexia through gene expression patterns. These results are useful for evaluating the complex efficacy of various active components of herbal medicines and their prescriptions. In addition, it can be predicted in the form of an in vitro test compared to the evaluation method using clinical and animal tests, which is costly and time-consuming. Therefore, the experimental method combining network pharmacology and microarray can be used as a useful tool for analyzing multiple efficacies of herbal medicines and prescriptions and selecting active components.

Availability of data and materials

All data generated or analyzed during this study are included in this published article and its supplementary information files.

Abbreviations

SDT:

Sipjeondaebo-tang

HYT:

Hyangsayukgunja-tang

MCH:

Melanin-concentrating hormone

CART:

Cocaine- and amphetamine-regulated transcript

NPY:

Neuropeptide Y

AGRP:

Melanocortins and agouti-related peptide

PYY:

Peptide YY

CCK:

Cholecystokinin

TdT:

Terminal deoxynucleotidyl transferase

DEGs:

Differentially expressed genes

CRH:

Corticotropin-releasing hormone

5-HT:

5-Hydroxytryptamine (serotonin)

References

  1. Kang YH (2008) Encyclopedia of life sciences, 1st edn. Academy book, Seoul

    Google Scholar 

  2. Morley JE (2002) Pathophysiology of anorexia. Clin Geriatr Med 18:661–673

    PubMed  Google Scholar 

  3. Woerwag-Mehta S, Treasure J (2008) Causes of anorexia nervosa. Psychiatry 7:147–151

    Google Scholar 

  4. Nahar B, Hossain M, Ickes SB, Naila NN, Mahfuz M, Hossain D, Denno DM, Walson J, Ahmed T (2019) Development and validation of a tool to assess appetite of children in low income settings. Appetite 134:182–192

    PubMed  Google Scholar 

  5. Arora S (2006) Role of neuropeptides in appetite regulation and obesity–a review. Neuropeptides 40:375–401

    CAS  PubMed  Google Scholar 

  6. Cheon C, Kang S, Ko Y, Kim M, Jang BH, Shin YC, Ko SG (2018) Sipjeondaebo-tang in patients with breast cancer with fatigue: a protocol for a pilot, randomised, double-blind, placebo-controlled, cross-over trial. BMJ open 8:e021242

    PubMed  PubMed Central  Google Scholar 

  7. Oh S, Cheon C, Park S, Jang B-H, Park JS, Jang S, Shin YC, Ko SG (2014) The analysis of the recent research trend of Sipjeondabo-tang in Korea. J Soc Prev Korean Med 18:113–123

    Google Scholar 

  8. Seo C, Shin H (2015) Quantitative analysis of Hyangsayukgunja-tang using an ultra-performance liquid chromatography coupled to electrospray ionization tandem mass spectrometry. Korean J Pharmacognosy 46:352–364

    Google Scholar 

  9. Davis AP, Grondin CJ, Johnson RJ, Sciaky D, Wiegers J, Wiegers TC, Mattingly CJ (2021) Comparative toxicogenomics database (CTD): update 2021. Nucleic Acids Res 49:D1138–d1143

    CAS  PubMed  Google Scholar 

  10. Huang Y, Fang J, Lu W, Wang Z, Wang Q, Hou Y, Jiang X, Reizes O, Lathia J, Nussinov R, Eng C, Cheng F (2019) A Systems Pharmacology Approach uncovers Wogonoside as an angiogenesis inhibitor of Triple-Negative breast Cancer by targeting hedgehog signaling. Cell Chem Biol 26:1143–1158e1146

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Mendez D, Gaulton A, Bento AP, Chambers J, De Veij M, Félix E, Magariños MP, Mosquera JF, Mutowo P, Nowotka M, Gordillo-Marañón M, Hunter F, Junco L, Mugumbate G, Rodriguez-Lopez M, Atkinson F, Bosc N, Radoux CJ, Segura-Cabrera A, Hersey A, Leach AR (2019) ChEMBL: towards direct deposition of bioassay data. Nucleic Acids Res 47:D930–d940

    CAS  PubMed  Google Scholar 

  12. Gilson MK, Liu T, Baitaluk M, Nicola G, Hwang L, Chong J (2016) BindingDB in 2015: a public database for medicinal chemistry, computational chemistry and systems pharmacology. Nucleic Acids Res 44:D1045–1053

    CAS  PubMed  Google Scholar 

  13. Szklarczyk D, Santos A, von Mering C, Jensen LJ, Bork P, Kuhn M (2016) STITCH 5: augmenting protein-chemical interaction networks with tissue and affinity data. Nucleic Acids Res 44:D380–384

    CAS  PubMed  Google Scholar 

  14. Yan D, Zheng G, Wang C, Chen Z, Mao T, Gao J, Yan Y, Chen X, Ji X, Yu J, Mo S, Wen H, Han W, Zhou M, Wang Y, Wang J, Tang K, Cao Z (2021) HIT 2.0: an enhanced platform for herbal ingredients’ targets. Nucleic Acids Res 50:D1238–D1243

    PubMed Central  Google Scholar 

  15. Huang L, Xie D, Yu Y, Liu H, Shi Y, Shi T, Wen C (2018) TCMID 2.0: a comprehensive resource for TCM. Nucleic Acids Res 46:D1117–d1120

    CAS  PubMed  Google Scholar 

  16. Kanehisa M, Furumichi M, Tanabe M, Sato Y, Morishima K (2017) KEGG: new perspectives on genomes, pathways, diseases and drugs. Nucleic Acids Res 45:D353–d361

    CAS  PubMed  Google Scholar 

  17. Yoshioka H, Fukaya S, Miura N, Onosaka S, Nonogaki T, Nagatsu A (2016) Suppressive effect of kampo formula juzen-taiho-to on carbon tetrachloride-induced hepatotoxicity in mice. Biol Pharm Bull 39:1564–1567

    CAS  PubMed  Google Scholar 

  18. Nakamoto H, Mimura T, Honda N (2008) Orally administrated Juzen-taiho‐to/TJ‐48 ameliorates erythropoietin (rHuEPO)‐resistant anemia in patients on hemodialysis. Hemodial Int 12:S9–S14

    PubMed  Google Scholar 

  19. Cheon C, Yoo JE, Yoo HS, Cho CK, Kang S, Kim M, Jang BH, Shin YC, Ko SG (2017) Efficacy and safety of sipjeondaebo-tang for anorexia in patients with cancer: a pilot, randomized, double-blind, placebo-controlled trial. Evidence-Based Complement  Alternat Med 2017:8780325. https://doi.org/10.1155/2017/8780325

    Article  Google Scholar 

  20. Motoo Y, Cameron S (2022) Kampo medicines for supportive care of patients with cancer: a brief review. Integr Med Res 11:100839

    PubMed  PubMed Central  Google Scholar 

  21. Zhang X, Qiu H, Li C, Cai P, Qi F (2021) The positive role of traditional chinese medicine as an adjunctive therapy for cancer. Biosci Trends 15:283–298

    CAS  PubMed  Google Scholar 

  22. Hattori T, Yakabi K, Takeda H (2013) Cisplatin-induced anorexia and ghrelin. Vitamins & Hormones 92:301–317

    CAS  Google Scholar 

  23. Kang HJ, Jeong MK, Park SJ, Jun HJ, Yoo HS (2019) Efficacy and safety of Yukgunja-Tang for treating anorexia in patients with cancer: the protocol for a pilot, randomized, controlled trial. Medicine 98(40):e16950

    PubMed  PubMed Central  Google Scholar 

  24. Ko MH, Song SY, Ha SJ, Lee JY, Yoon SW, Park JH, Park SJ, Yoo HS (2021) Efficacy and safety of yukgunja-tang for patients with cancer-related anorexia: a randomized, controlled trial, pilot study. Integr Cancer Ther 20:15347354211019107

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Lee JH, Bae K, Yoo HS, Lee JH, Bae K, Yoo H-S (2017) The effect of traditional oriental herbal medicine for anorexia in cancer patients: a systematic review. J Korean Med 38:8–20

    Google Scholar 

  26. Lee SJ, Ha JB, Yoo JH (2020) A case study of Parkinson’s Disease patient with anorexia and nausea treated with korean-medicine treatment including Hyangsayukgunja-tang. J Intern Korean Med 41:717–723

    Google Scholar 

  27. Shinohara Y, Nishino Y, Yamanaka M, Ohmori K, Elbadawy M, Usui T, Sasaki K (2019) Efficacy of Juzen-taiho-to against vincristine-induced toxicity in dogs. J Vet Med Sci 81:1810–1816

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Shinohara Y, Elbadawy M, Yamanaka M, Yamamoto H, Abugomaa A, Usui T, Sasaki K (2022) Effect of the liquid form of traditional chinese medicine, Hozen-S, on gastric motility in dogs. J Vet Med Sci 84:841–846

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Takeda H, Muto S, Nakagawa K, Ohnishi S, Asaka M (2012) Rikkunshito and ghrelin secretion. Curr Pharm Design 18:4827–4838

    CAS  Google Scholar 

  30. Yada T, Kohno D, Maejima Y, Sedbazar U, Arai T, Toriya M, Maekawa F, Kurita H, Niijima A, Yakabi K (2012) Neurohormones, rikkunshito and hypothalamic neurons interactively control appetite and anorexia. Curr Pharm Design 18:4854–4864

    CAS  Google Scholar 

  31. Kalra SP, Dube MG, Sahu A, Phelps CP, Kalra PS (1991) Neuropeptide Y secretion increases in the paraventricular nucleus in association with increased appetite for food. Proc Nat Acad Sci 88:10931–10935

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Stanley BG, Kyrkouli SE, Lampert S, Leibowitz SF (1986) Neuropeptide Y chronically injected into the hypothalamus: a powerful neurochemical inducer of hyperphagia and obesity. Peptides 7:1189–1192

    CAS  PubMed  Google Scholar 

  33. Quiñones M, Al-Massadi O, Gallego R, Fernø J, Diéguez C, López M, Nogueiras R (2015) Hypothalamic CaMKKβ mediates glucagon anorectic effect and its diet-induced resistance. Mol Metabolism 4:961–970

    Google Scholar 

  34. Schulman JL, Carleton JL, Whitney G, Whitehorn JC (1957) Effect of glucagon on food intake and body weight in man. J Appl Physiol 11:419–421

    CAS  PubMed  Google Scholar 

  35. Penick SB, Hinkle LE Jr, Paulsen EG (1961) Depression of food intake induced in healthy subjects by glucagon. N Engl J Med 264:893–897

    CAS  PubMed  Google Scholar 

  36. Al-Massadi O, Fernø J, Diéguez C, Nogueiras R, Quiñones M (2019) Glucagon control on food intake and energy balance. Int J Mol Sci 20:3905

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Kumai M, Tamai H, Fujii S, Nakagawa T, Aoki TT (1988) Glucagon secretion in anorexia nervosa. Am J Clin Nutr 47:239–242

    CAS  PubMed  Google Scholar 

  38. Howard D, Negraes P, Voineskos AN, Kaplan AS, Muotri AR, Duvvuri V, French L (2020) Molecular neuroanatomy of anorexia nervosa. Sci Rep 10:11411

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Delint-Ramirez I, Willoughby D, Hammond GV, Ayling LJ, Cooper DM (2011) Palmitoylation targets AKAP79 protein to lipid rafts and promotes its regulation of calcium-sensitive adenylyl cyclase type 8. J Biol Chem 286:32962–32975

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Feltrin KL, Little TJ, Meyer JH, Horowitz M, Rades T, Wishart J, Feinle-Bisset C (2008) Comparative effects of intraduodenal infusions of lauric and oleic acids on antropyloroduodenal motility, plasma cholecystokinin and peptide YY, appetite, and energy intake in healthy men. Am J Clin Nutr 87:1181–1187

    CAS  PubMed  Google Scholar 

  41. de Haro-Licer J, Roura-Moreno J, Vizitiu A, González-Fernández A, González-Ares JA (2013) Long term serious olfactory loss in colds and/or flu. Acta Otorrinolaringologica (English Edition) 64:331–338

    Google Scholar 

  42. Fluitman K, Nadar H, Roos D, Berendse H, Keijser B, Nieuwdorp M, Ijzerman R, Visser M (2019) The association of olfactory function with BMI, appetite, and prospective weight change in dutch community-dwelling older adults. J Nutr Health Aging 23:746–752

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Connor EE, Zhou Y, Liu GE (2018) The essence of appetite: does olfactory receptor variation play a role? J Anim Sci 96:1551–1558

    PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This research was supported by a grant (21173MFDS561) from the Ministry of Food and Drug Safety in 2023.

Author information

Author notes

  1. Ji Hwan Lee and Dongyeop Jang contributed equally to this work.

Authors and Affiliations

  1. Department of Preventive Medicine, College of Korean Medicine, Gachon University, 1342, Seongnamdaero, Seongnam, 13120, Republic of Korea

    Ji Hwan Lee, Myong Jin Lee, Myoung-Sook Shin & Ki Sung Kang

  2. Vital to Life Co. Ltd, 1342, Seongnamdaero, Seongnam, 13120, Republic of Korea

    Ji Hwan Lee & Jun Yeon Park

  3. Department of Physiology, College of Korean Medicine, Gachon University, 1342, Seongnamdaero,, Seongnam, 13120, Republic of Korea

    Dongyeop Jang & Chang-Eop Kim

  4. Department of Food Science and Biotechnology, Kyonggi University, Suwon, 16227, Republic of Korea

    Jun Yeon Park

Authors
  1. Ji Hwan Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dongyeop Jang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Myong Jin Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Myoung-Sook Shin
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chang-Eop Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Yeon Park
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ki Sung Kang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KSK, CEK, and JYP conceived and designed the experiments; DJ and MJL performed the experiments; DJ, MJL, JHL, and MSS analyzed the data; and JHL and DJ wrote the manuscript. All authors have read and approved the final manuscript.

Corresponding authors

Correspondence to Jun Yeon Park or Ki Sung Kang.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1:

 Figure S1. Volume plots for each sample. Each dot indicates a single gene. The x-axis and y-axis indicate volume and log2 fold change, respectively. The volume (intensity) of the expression value is defined as the geometric mean of the expression values of the two groups. Table S1. Compounds associated with anorexia-associated differently expressed genes.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lee, J.H., Jang, D., Lee, M.J. et al. Regulation of appetite-related neuropeptides by herbal medicines: research using microarray and network pharmacology. Appl Biol Chem 66, 68 (2023). https://doi.org/10.1186/s13765-023-00826-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13765-023-00826-x

Keywords