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Whey protein hydrolysates improve high-fat-diet-induced obesity by modulating the brain–peripheral axis of GLP-1 through inhibition of DPP-4 function in mice

  • Original Contribution
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European Journal of Nutrition Aims and scope Submit manuscript

Abstract

Purpose

Obesity is a growing global health concern. Recent literature indicates a prominent role of glucagon-like peptide-1 (GLP-1) in glucose metabolism and food intake. The synergistic action of GLP-1 in the gut and brain is responsible for its satiety-inducing effect, suggesting that upregulation of active GLP-1 levels could be an alternative strategy to combat obesity. Dipeptidyl peptidase-4 (DPP-4) is an exopeptidase known to inactivate GLP-1, suggesting that its inhibition could be a crucial strategy for effectively extending the half-life of endogenous GLP-1. Peptides derived from partial hydrolysis of dietary proteins are gaining traction due to their inhibitory activity on DPP-4.

Methods

Whey protein hydrolysate from bovine milk (bmWPH) was produced using simulated in situ digestion, purified using RP-HPLC, and characterized for DPP-4 inhibition. The antiadipogenic and antiobesity activity of bmWPH was then studied in 3T3-L1 preadipocytes and high-fat diet-induced obesity (HFD) mice model, respectively.

Results

The dose-dependent inhibitory effect of bmWPH on the catalytic activity of DPP-4 was observed. Additionally, bmWPH suppressed adipogenic transcription factors and DPP-4 protein levels, leading to a negative effect on preadipocyte differentiation. In an HFD mice model, co-administration of WPH for 20 weeks downregulated adipogenic transcription factors, resulting in a concomitant reduction in whole body weight and adipose tissues. Mice fed with bmWPH also showed a marked reduction in DPP-4 levels in WAT, liver, and serum. Furthermore, HFD mice fed with bmWPH exhibited increased serum and brain GLP levels, which led to a significant decrease in food intake.

Conclusion

In conclusion, bmWPH reduces body weight in HFD mice by suppressing appetite through GLP-1, a satiety-inducing hormone, in both the brain and peripheral circulation. This effect is achieved through modulation of both the catalytic and non-catalytic activity of DPP-4.

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Data availability

The datasets generated and analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Miralpeix C, Reguera AC, Fosch A et al (2021) Hypothalamic endocannabinoids in obesity: an old story with new challenges. Cell Mol Life Sci 78(23):7469–7490. https://doi.org/10.1007/s00018-021-04002-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. van Bloemendaal L, ten Kulve JS, La Fleur SE et al (2014) Effects of glucagon-like peptide 1 on appetite and body weight: focus on the CNS. J Endocrinol 221(1):T1-16. https://doi.org/10.1530/JOE-13-0414

    Article  CAS  PubMed  Google Scholar 

  3. Schroeder LE, Leinninger GM (2018) Role of central neurotensin in regulating feeding: Implications for the development and treatment of body weight disorders. Biochim Biophys Acta—Mol Basis Dis 1864(3):900–916. https://doi.org/10.1016/j.bbadis.2017.12.036

  4. Bauer PV, Hamr SC, Duca FA (2016) Regulation of energy balance by a gut-brain axis and involvement of the gut microbiota. Cell Mol Life Sci 73(4):737–755. https://doi.org/10.1007/s00018-015-2083-z

    Article  CAS  PubMed  Google Scholar 

  5. Batterham RL, Cowley MA, Small CJ et al (2002) Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 418:650–654. https://doi.org/10.1038/NATURE00887

    Article  CAS  PubMed  Google Scholar 

  6. Holst JJ (1994) Glucagonlike peptide 1: a newly discovered gastrointestinal hormone. Gastroenterology 107(6):1848–1855. https://doi.org/10.1016/0016-5085(94)90831-1

    Article  CAS  PubMed  Google Scholar 

  7. Drucker DJ (1998) Perspectives in diabetes: glucagon-like peptides. Diabetes 47(2):159–169. https://doi.org/10.2337/diab.47.2.159

    Article  CAS  PubMed  Google Scholar 

  8. Farooqui AA, Farooqui T, Panza F, Frisardi V (2012) Metabolic syndrome as a risk factor for neurological disorders. Cell Mol Life Sci 69(5):741–762. https://doi.org/10.1007/s00018-011-0840-1

    Article  CAS  PubMed  Google Scholar 

  9. Tsang AH, Nuzzaci D, Darwish T et al (2020) Nutrient sensing in the nucleus of the solitary tract mediates non-aversive suppression of feeding via inhibition of AgRP neurons. Mol Metab 42:101070. https://doi.org/10.1016/j.molmet.2020.101070

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Brierley DI, Holt MK, Singh A et al (2021) Central and peripheral GLP-1 systems independently suppress eating. Nat Metab 3:258–273. https://doi.org/10.1038/s42255-021-00344-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Dakin CL, Gunn I, Small CJ et al (2001) Oxyntomodulin inhibits food intake in the rat. Endocrinology 142:4244–4250. https://doi.org/10.1210/ENDO.142.10.8430

    Article  CAS  PubMed  Google Scholar 

  12. Panjwani N, Mulvihill EE, Longuet C et al (2013) GLP-1 receptor activation indirectly reduces hepatic lipid accumulation but does not attenuate development of atherosclerosis in diabetic male ApoE −/− mice. Endocrinology 154(1):127–139. https://doi.org/10.1210/en.2012-1937

    Article  CAS  PubMed  Google Scholar 

  13. Le Roux CW, Aylwin SJB, Batterham RL et al (2006) Gut hormone profiles following bariatric surgery favor an anorectic state, facilitate weight loss, and improve metabolic parameters. Ann Surg 243:108–114. https://doi.org/10.1097/01.SLA.0000183349.16877.84

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lamers D, Famulla S, Wronkowitz N et al (2011) Dipeptidyl peptidase 4 is a novel adipokine potentially linking obesity to the metabolic syndrome. Diabetes 60:1917–1925. https://doi.org/10.2337/DB10-1707

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wronkowitz N, Görgens SW, Romacho T et al (1842) (2014) Soluble DPP4 induces inflammation and proliferation of human smooth muscle cells via protease-activated receptor 2. Biochim Biophys Acta - Mol Basis Dis 9:1613–1621. https://doi.org/10.1016/j.bbadis.2014.06.004

    Article  CAS  Google Scholar 

  16. Chou E, Suzuma I, Way KJ et al (2002) Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation 105:373–379. https://doi.org/10.1161/HC0302.102143

    Article  CAS  PubMed  Google Scholar 

  17. Yoon YS, Uchida S, Masuo O et al (2005) Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy: restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. Circulation 111:2073–2085. https://doi.org/10.1161/01.CIR.0000162472.52990.36

    Article  CAS  PubMed  Google Scholar 

  18. Zhong J, Maiseyeu A, Davis SN, Rajagopalan S (2015) DPP4 in cardiometabolic disease: recent insights from the laboratory and clinical trials of DPP4 inhibition. Circ Res 116(8):1491–1504. https://doi.org/10.1161/CIRCRESAHA.116.305665

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Knudsen LB (2019) Inventing liraglutide, a glucagon-like peptide-1 analogue, for the treatment of diabetes and obesity. ACS Pharmacol Transl Sci 2:468–484. https://doi.org/10.1021/ACSPTSCI.9B00048

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gregoire FM, Smas CM, Sul HS (1998) Understanding adipocyte differentiation. Physiol Rev 78(3):783–809. https://doi.org/10.1152/physrev.1998.78.3.783

    Article  CAS  PubMed  Google Scholar 

  21. Jakab J, Miškić B, Mikšić Š, et al (2021) Adipogenesis as a potential anti-obesity target: A review of pharmacological treatment and natural products. Diabetes Metab Syndr Obes Targets Ther 14:67–83. https://doi.org/10.2147/DMSO.S281186. (eCollection 2021)

  22. Mauro M, Taylor V, Wharton S, Sharma AM (2008) Barriers to obesity treatment. Eur J Intern Med 19:173–180. https://doi.org/10.1016/J.EJIM.2007.09.011

    Article  PubMed  Google Scholar 

  23. Konstantinidi M, Koutelidakis AE (2019) Functional foods and bioactive compounds: a review of its possible role on weight management and obesity’s metabolic consequences. Medicines 6(3):94. https://doi.org/10.3390/medicines6030094

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chuang CC, Martinez K, Xie G et al (2010) Quercetin is equally or more effective than resveratrol in attenuating tumor necrosis factor-α-mediated inflammation and insulin resistance in primary human adipocytes. Am J Clin Nutr 92(6):1511–1521. https://doi.org/10.3945/ajcn.2010.29807

    Article  CAS  PubMed  Google Scholar 

  25. van Heerden FR (2008) Hoodia gordonii: a natural appetite suppressant. J Ethnopharmacol 119(3):434–437. https://doi.org/10.1016/j.jep.2008.08.023

    Article  PubMed  Google Scholar 

  26. Hall WL, Millward DJ, Long SJ, Morgan LM (2003) Casein and whey exert different effects on plasma amino acid profiles, gastrointestinal hormone secretion and appetite. Br J Nutr 89:239–248. https://doi.org/10.1079/BJN2002760

    Article  CAS  PubMed  Google Scholar 

  27. Westerterp-Plantenga MS, Nieuwenhuizen A, Tomé D et al (2009) Dietary protein, weight loss, and weight maintenance. Annu Rev Nutr 29:21–41. https://doi.org/10.1146/ANNUREV-NUTR-080508-141056

    Article  CAS  PubMed  Google Scholar 

  28. Ewert J, Luz A, Volk V et al (2019) Enzymatic production of emulsifying whey protein hydrolysates without the need of heat inactivation. J Sci Food Agric 99:3443–3450. https://doi.org/10.1002/JSFA.9562

    Article  CAS  PubMed  Google Scholar 

  29. Krissansen GW (2007) Emerging health properties of whey proteins and their clinical implications. J Am Coll Nutr 26(6):713S-S723. https://doi.org/10.1080/07315724.2007.10719652

    Article  CAS  PubMed  Google Scholar 

  30. Jeewanthi RKC, Kim MH, Lee NK et al (2017) peptide analysis and the bioactivity of whey protein hydrolysates from cheese whey with several enzymes. Korean J food Sci Anim Resour 37:62–70. https://doi.org/10.5851/KOSFA.2017.37.1.62

    Article  PubMed  PubMed Central  Google Scholar 

  31. Nongonierma AB, Lalmahomed M, Paolella S, FitzGerald RJ (2017) Milk protein isolate (MPI) as a source of dipeptidyl peptidase IV (DPP-IV) inhibitory peptides. Food Chem 231:202–211. https://doi.org/10.1016/J.FOODCHEM.2017.03.123

    Article  CAS  PubMed  Google Scholar 

  32. Bendtsen LQ, Lorenzen JK, Bendsen NT et al (2013) Effect of dairy proteins on appetite, energy expenditure, body weight, and composition: a review of the evidence from controlled clinical trials. Adv Nutr 4(4):418–438. https://doi.org/10.3945/an.113.003723

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Walsh DJ, Bernard H, Murray BA et al (2004) In vitro generation and stability of the lactokinin β-lactoglobulin fragment (142–148). J Dairy Sci 87: (11):3845–57. https://doi.org/10.3168/jds.S0022-0302(04)73524-

    Article  CAS  PubMed  Google Scholar 

  34. Majid A, Lakshmikanth M, Lokanath NK, Poornima Priyadarshini CG (2022) Generation, characterization and molecular binding mechanism of novel dipeptidyl peptidase-4 inhibitory peptides from sorghum bicolor seed protein. Food Chem 369:130888. https://doi.org/10.1016/j.foodchem.2021.130888

    Article  CAS  PubMed  Google Scholar 

  35. Kumar R, Joshi R, Kumari M et al (2020) Elevated CO2 and temperature influence key proteins and metabolites associated with photosynthesis, antioxidant and carbon metabolism in Picrorhiza kurroa. J Proteomics 219:103755. https://doi.org/10.1016/j.jprot.2020.103755

    Article  CAS  PubMed  Google Scholar 

  36. Rai C, Nandini CD, Priyadarshini P (2021) Composition and structure elucidation of bovine milk glycosaminoglycans and their anti-adipogenic activity via modulation PPAR-γ and C/EBP-α. Int J Biol Macromol 193(Pt A):137–144. https://doi.org/10.1016/j.ijbiomac.2021.10.076

    Article  CAS  PubMed  Google Scholar 

  37. Wang CY, Liao JK (2012) A mouse model of diet-induced obesity and insulin resistance. Methods Mol Biol 821:421–433. https://doi.org/10.1007/978-1-61779-430-8_27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Fischer AH, Jacobson K, Rose J, Zeller R (2005) Hematoxylin and Eosin ( H & E ) staining. CSH Protoc. https://doi.org/10.1101/pdb.prot4986

    Article  Google Scholar 

  39. Bird B, Rowlette J (2017) A protocol for rapid, label-free histochemical imaging of fibrotic liver. Analyst 142(8):1179–1184. https://doi.org/10.1039/c6an02080a

    Article  CAS  PubMed  Google Scholar 

  40. Zilleßen P, Celner J, Kretschmann A et al (2016) Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre)adipocytes. Sci Rep 6:23074. https://doi.org/10.1038/srep23074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Frid AH, Nilsson M, Holst JJ, Björck IME (2005) Effect of whey on blood glucose and insulin responses to composite breakfast and lunch meals in type 2 diabetic subjects. Am J Clin Nutr 82(1):69–75. https://doi.org/10.1093/ajcn/82.1.69

    Article  CAS  PubMed  Google Scholar 

  42. Minj S, Anand S (2020) Whey proteins and its derivatives: Bioactivity, functionality, and current applications. Dairy 1(3):233–258. https://pubmed.ncbi.nlm.nih.gov/?term=Minj%2C+S.%2C+%26+Anand%2C+S.+%282020%29.+Whey+proteins+and+its+derivatives%3A+Bioactivity%2C+functionality%2C+and+current+applications.+Dairy%2C+1%283%29%2C+233-258. Accessed 9 Mar 2022

  43. Nongonierma AB, Cadamuro C, Le Gouic A et al (2019) Dipeptidyl peptidase IV (DPP-IV) inhibitory properties of a camel whey protein enriched hydrolysate preparation. Food Chem 279:70–79. https://doi.org/10.1016/j.foodchem.2018.11.142

    Article  CAS  PubMed  Google Scholar 

  44. Nongonierma AB, Mazzocchi C, Paolella S, FitzGerald RJ (2017) Release of dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from milk protein isolate (MPI) during enzymatic hydrolysis. Food Res Int 94:79–89. https://doi.org/10.1016/j.foodres.2017.02.004

    Article  CAS  PubMed  Google Scholar 

  45. Song JJ, Wang Q, Du M et al (2017) Identification of dipeptidyl peptidase-IV inhibitory peptides from mare whey protein hydrolysates. J Dairy Sci 100(9):6885–6894. https://doi.org/10.3168/jds.2016-11828

    Article  CAS  PubMed  Google Scholar 

  46. Çakır B, Okuyan B, Şener G, Tunali-Akbay T (2021) Investigation of beta-lactoglobulin derived bioactive peptides against SARS-CoV-2 (COVID-19): in silico analysis. Eur J Pharmacol 891:173781. https://doi.org/10.1016/j.ejphar.2020.173781

    Article  CAS  PubMed  Google Scholar 

  47. Martínez-Sánchez SM, Gabaldón-Hernández JA, Montoro-García S (2020) Unravelling the molecular mechanisms associated with the role of food-derived bioactive peptides in promoting cardiovascular health. J Funct Foods. https://doi.org/10.1016/j.jff.2019.103645

    Article  Google Scholar 

  48. Roberts PR, Burney JD, Black KW, Zaloga GP (1999) Effect of chain length on absorption of biologically active peptides from the gastrointestinal tract. Digestion 60(4):332–337. https://doi.org/10.1159/000007679

    Article  CAS  PubMed  Google Scholar 

  49. Das SS, Hayashi H, Sato T et al (2014) Regulation of dipeptidyl peptidase 4 production in adipocytes by glucose. Diabetes, Metab Syndr Obes Targets Ther 7:185–194. https://doi.org/10.2147/DMSO.S62610

    Article  CAS  Google Scholar 

  50. Jiang S, Wu X, Wang Y et al (2020) The potential DPP-4 inhibitors from Xiao-Ke-An improve the glucolipid metabolism via the activation of AKT/GSK-3β pathway. Eur J Pharmacol 882. https://doi.org/10.1016/j.ejphar.2020.173272

    Article  PubMed  Google Scholar 

  51. Jiang S, Wu X, Wang Y et al (2020) The potential DPP-4 inhibitors from Xiao-Ke-An improve the glucolipid metabolism via the activation of AKT/GSK-3β pathway. Eur J Pharmacol 882:173272. https://doi.org/10.1016/j.ejphar.2020.173272

    Article  CAS  PubMed  Google Scholar 

  52. D’souza K, Mercer A, Mawhinney H et al (2020) Whey peptides stimulate differentiation and lipid metabolism in adipocytes and ameliorate lipotoxicity-induced insulin resistance in muscle cells. Nutrients 12(2):425. https://doi.org/10.3390/nu12020425

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. de Castro RJS, Inacio RF, de Oliveira ALR, Sato HH (2016) Statistical optimization of protein hydrolysis using mixture design: development of efficient systems for suppression of lipid accumulation in 3T3-L1 adipocytes. Biocatal Agric Biotechnol 5:17–23. https://doi.org/10.1016/j.bcab.2015.12.004

    Article  Google Scholar 

  54. Karami Z, Akbari-adergani B (2019) Bioactive food derived peptides: a review on correlation between structure of bioactive peptides and their functional properties. J Food Sci Technol 56(2):535–547

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Takeda K, Sawazaki H, Takahashi H et al (2018) The dipeptidyl peptidase-4 (DPP-4) inhibitor teneligliptin enhances brown adipose tissue function, thereby preventing obesity in mice. FEBS Open Bio 8(11):1782–1793. https://doi.org/10.1002/2211-5463.12498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Beiroa D, Imbernon M, Gallego R et al (2014) GLP-1 agonism stimulates brown adipose tissue thermogenesis and browning through hypothalamic AMPK. Diabetes 63(10):3346–3358. https://doi.org/10.2337/db14-0302

    Article  CAS  PubMed  Google Scholar 

  57. Klemann C, Wagner L, Stephan M, von Hörsten S (2016) Cut to the chase: a review of CD26/dipeptidyl peptidase-4’s (DPP4) entanglement in the immune system. Clin Exp Immunol 185(1):1–21. https://doi.org/10.1111/cei.12781

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu F, Zhu X, Jiang X et al (2022) Transcriptional control by HNF-1: Emerging evidence showing its role in lipid metabolism and lipid metabolism disorders. Genes Dis 9(5):1248–1257. https://doi.org/10.1016/j.gendis.2021.06.010.eCollection

    Article  CAS  PubMed  Google Scholar 

  59. ͆lusarz A, Pulakat L, (2015) The two faces of miR-29. J Cardiovasc Med 16(7):480–490. https://doi.org/10.2459/JCM.0000000000000246

    Article  CAS  Google Scholar 

  60. Turcot V, Bouchard L, Faucher G et al (2011) DPP4 gene DNA methylation in the omentum is associated with its gene expression and plasma lipid profile in severe obesity. Obesity 19(2):388–395. https://doi.org/10.1038/oby.2010.198

    Article  CAS  PubMed  Google Scholar 

  61. Xu SP, Mao XY, Ren FZ, Che HL (2011) Attenuating effect of casein glycomacropeptide on proliferation, differentiation, and lipid accumulation of in vitro Sprague-Dawley rat preadipocytes. J Dairy Sci 94(2):676–683. https://doi.org/10.3168/jds.2010-3827

    Article  CAS  PubMed  Google Scholar 

  62. Kim YM, Kim IH, Choi JW et al (2015) The anti-obesity effects of a tuna peptide on 3T3-L1 adipocytes are mediated by the inhibition of the expression of lipogenic and adipogenic genes and by the activation of the Wnt/β-catenin signaling pathway. Int J Mol Med 36(2):327–334. https://doi.org/10.3892/ijmm.2015.2231

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhang X, Shi W, He H et al (2020) Hypolipidemic effects and mechanisms of Val-Phe-Val-Arg-Asn in C57BL/6J mice and 3T3-L1 cell models. J Funct Foods 73:104100. https://doi.org/10.1016/j.jff.2020.104100

    Article  CAS  Google Scholar 

  64. Chakrabarti S, Wu J (2015) Milk-derived tripeptides IPP (Ile-Pro-Pro) and VPP (Val-Pro- Pro) promote adipocyte differentiation and inhibit inflammation in 3T3-F442A cells. PLoS One 10(2):e0117492. https://doi.org/10.1371/journal.pone.0117492

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Pratley RE, Salsali A (2007) Inhibition of DPP-4: a new therapeutic approach for the treatment of type 2 diabetes. Curr Med Res Opin 23(4):919–931. https://doi.org/10.1185/030079906x162746

    Article  CAS  PubMed  Google Scholar 

  66. Gutzwiller JP, Drewe J, Göke B et al (1999) Glucagon-like peptide-1 promotes satiety and reduces food intake in patients with diabetes mellitus type 2. Am J Physiol—Regul Integr Comp Physiol 276(5):R1541–R1544. https://doi.org/10.1152/ajpregu.1999.276.5.r1541

    Article  CAS  Google Scholar 

  67. de Fonseca RR, Navarro M, Alvarez E et al (2000) Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism 49(6):709–717. https://doi.org/10.1053/meta.2000.6251

    Article  Google Scholar 

  68. Abbott CR, Monteiro M, Small CJ et al (2005) The inhibitory effects of peripheral administration of peptide YY 3–36 and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res 1044(1):127–131. https://doi.org/10.1016/j.brainres.2005.03.011

    Article  CAS  PubMed  Google Scholar 

  69. Marguet D, Baggio L, Kobayashi T et al (2000) Enhanced insulin secretion and improved glucose tolerance in mice lacking CD26. Proc Natl Acad Sci USA 97(12):6874–6879. https://doi.org/10.1073/pnas.120069197

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Katsuyama H, Adachi H, Hamasaki H, et al (2014) Significant differences in effects of sitagliptin treatment on body weight and lipid metabolism between obese and non-obese patients with type 2 diabetes. J Endocrinol Metab 4:136–142. https://doi.org/10.14740/jem243w

  71. Chae YN, Kim TH, Kim MK et al (2015) Beneficial effects of evogliptin, a novel dipeptidyl peptidase 4 inhibitor, on adiposity with increased Ppargc1a in white adipose tissue in obese mice. PLoS One 10(12):e0144064. https://doi.org/10.1371/journal.pone.0144064

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Deacon CF, Pridal L, Klarskov L et al (1996) Glucagon-like peptide 1 undergoes differential tissue-specific metabolism in the anesthetized pig. Am J Physiol—Endocrinol Metab 271(3 Pt 1):E458–E464. https://doi.org/10.1152/ajpendo.1996.271.3.e458

    Article  CAS  Google Scholar 

  73. Wang X, Ke J, Zhu Y, Jun et al (2021) Dipeptidyl peptidase-4 (DPP4) inhibitor sitagliptin alleviates liver inflammation of diabetic mice by acting as a ROS scavenger and inhibiting the NFκB pathway. Cell Death Discov 7(1):236. https://doi.org/10.1038/s41420-021-00625-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Berthoud HR, Albaugh VL, Neuhuber WL (2021) Gut-brain communication and obesity: Understanding functions of the vagus nerve. J Clin Invest 131(10):e143770. https://doi.org/10.1172/JCI143770

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Ørskov C, Poulsen SS, Møller M, Holst JJ (1996) Glucagon-like peptide I receptors in the subfornical organ and the area postrema are accessible to circulating glucagon-like peptide I. Diabetes 45(6):832–835. https://doi.org/10.2337/diab.45.6.832

    Article  PubMed  Google Scholar 

  76. Korner J, Bessler M, Inabnet W et al (2007) Exaggerated glucagon-like peptide-1 and blunted glucose-dependent insulinotropic peptide secretion are associated with Roux-en-Y gastric bypass but not adjustable gastric banding. Surg Obes Relat Dis 3(6):597–601. https://doi.org/10.1016/j.soard.2007.08.004

    Article  PubMed  PubMed Central  Google Scholar 

  77. Whitcomb DC, Taylor IL (1992) A new twist in the brain-gut axis. Am J Med Sci 304(5):334–8. https://doi.org/10.1097/00000441-199211000-00001

    Article  CAS  PubMed  Google Scholar 

  78. Kastin AJ, Akerstrom V, Pan W (2002) Interactions of glucagon-like peptide-1 (GLP-1) with the blood-brain barrier. J Mol Neurosci 18(1–2):7–14. https://doi.org/10.1385/JMN:18:1-2:07

    Article  CAS  PubMed  Google Scholar 

  79. Brierley DI, Holt MK, Singh A et al (2021) Central and peripheral GLP-1 systems independently suppress eating. Nat Metab 3(2):258–273. https://doi.org/10.1038/s42255-021-00344-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Parker JA, McCullough KA, Field BCT et al (2013) Glucagon and GLP-1 inhibit food intake and increase c-fos expression in similar appetite regulating centres in the brainstem and amygdala. Int J Obes 37(10):1391–1398. https://doi.org/10.1038/ijo.2012.227

    Article  CAS  Google Scholar 

  81. Dalvi PS, Nazarians-Armavil A, Purser MJ, Belsham DD (2012) Glucagon-like peptide-1 receptor agonist, exendin-4, regulates feeding-associated neuropeptides in hypothalamic neurons in vivo and in vitro. Endocrinology 153(5):2208–2222. https://doi.org/10.1210/en.2011-1795

    Article  CAS  PubMed  Google Scholar 

  82. Yaribeygi H, Atkin SL, Sahebkar A (2019) Natural compounds with DPP-4 inhibitory effects: implications for the treatment of diabetes. J Cell Biochem 120(7):10909–10913. https://doi.org/10.1002/jcb.28467

    Article  CAS  PubMed  Google Scholar 

  83. Doupis J, Veves A (2008) DPP4 inhibitors: a new approach in diabetes treatment. Adv Ther 25(7):627–643. https://doi.org/10.1007/s12325-008-0076-1

    Article  CAS  PubMed  Google Scholar 

  84. Tulipano G, Sibilia V, Caroli AM, Cocchi D (2011) Whey proteins as source of dipeptidyl dipeptidase IV (dipeptidyl peptidase-4) inhibitors. Peptides 32(4):835–838. https://doi.org/10.1016/j.peptides.2011.01.002

    Article  CAS  PubMed  Google Scholar 

  85. Gaudel C, Nongonierma AB, Maher S et al (2013) A whey protein hydrolysate promotes insulinotropic activity in a clonal pancreatic β-cell line and enhances glycemic function in ob/ob mice. J Nutr 143(7):1109–1114. https://doi.org/10.3945/jn.113.174912

    Article  CAS  PubMed  Google Scholar 

  86. Marques AP, Cunha-Santos J, Leal H et al (1862) (2018) Dipeptidyl peptidase IV (DPP-IV) inhibition prevents fibrosis in adipose tissue of obese mice. Biochim Biophys Acta—Gen Subj 3:403–413. https://doi.org/10.1016/j.bbagen.2017.11.012

    Article  CAS  Google Scholar 

  87. Da Silva MS, Bigo C, Barbier O, Rudkowska I (2017) Whey protein hydrolysate and branched-chain amino acids downregulate inflammation-related genes in vascular endothelial cells. Nutr Res 38:43–51. https://doi.org/10.1016/j.nutres.2017.01.005

    Article  CAS  PubMed  Google Scholar 

  88. Ma Y, Liu J, Shi H, Yu L, (Lucy) (2016) Isolation and characterization of anti-inflammatory peptides derived from whey protein. J Dairy Sci 99(9):6902–6912. https://doi.org/10.3168/jds.2016-11186

    Article  CAS  PubMed  Google Scholar 

  89. Zeng Y, Li C, Guan M et al (2014) The DPP-4 inhibitor sitagliptin attenuates the progress of atherosclerosis in apolipoprotein-E-knockout mice via AMPK- and MAPK-dependent mechanisms. Cardiovasc Diabetol 13:32. https://doi.org/10.1186/1475-2840-13-32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Dobrian AD, Ma Q, Lindsay JW et al (2011) Dipeptidyl peptidase IV inhibitor sitagliptin reduces local inflammation in adipose tissue and in pancreatic islets of obese mice. Am J Physiol—Endocrinol Metab 300(2):E410–E421. https://doi.org/10.1152/ajpendo.00463.2010

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Dr. Robin Joshi from CSIR-IHBT for technical assistance with the LC-MS/MS analysis. The authors would like to thank Ms. Asha M, Sr. Technical Officer (3), CSIR-CFTRI, for technical assistance in preparatory HPLC. We acknowledge Dr. Madankumar P, Department of Biochemistry, and Dr. Gopinath, Department of Molecular Nutrition, for the valuable inputs and proofreading. The authors acknowledge the constant support of CSIR-CFTRI, Mysuru. Ms. Chaitra Rai is grateful to the Department of Biotechnology (DBT), Ministry of Science and Technology, Govt. of India, New Delhi, for the award of Research Fellowship and financial assistance under the project BT/PR10329/PFN/20/776/2013.

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Authors and Affiliations

  1. Department of Molecular Nutrition, CSIR-Central Food Technological Research Institute, Mysuru, 570020, Karnataka, India

    Chaitra Rai & Poornima Priyadarshini

  2. Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India

    Chaitra Rai & Poornima Priyadarshini

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  1. Chaitra Rai
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  2. Poornima Priyadarshini
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CR contributed to investigation, data curation, formal analysis, and writing—original draft. PP contributed to conceptualization, data curation, methodology, writing—review, funding acquisition and project administration.

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Correspondence to Poornima Priyadarshini.

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All procedures involving animals were performed according to protocols approved by the Institutional Animal Ethics Committee of CSIR-CFTRI, Mysore (IAEC Approval No: 190/2020).

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Rai, C., Priyadarshini, P. Whey protein hydrolysates improve high-fat-diet-induced obesity by modulating the brain–peripheral axis of GLP-1 through inhibition of DPP-4 function in mice. Eur J Nutr 62, 2489–2507 (2023). https://doi.org/10.1007/s00394-023-03162-4

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