{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T15:13:19Z","timestamp":1780672399741,"version":"3.54.1"},"reference-count":45,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T00:00:00Z","timestamp":1780617600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Yunnan Fundamental Research Projects","award":["202301AS070014"],"award-info":[{"award-number":["202301AS070014"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Foods"],"abstract":"<jats:p>Obesity and its metabolic complications represent a major global health challenge, and food-derived bioactive peptides are emerging as promising dietary interventions. In this study, two hemp seed protein-derived tetrapeptides with pancreatic lipase (PL) and cholesterol esterase (CE) inhibitory activity, APAM and RLPA, were co-administered with a high-fat diet (HFD) to male C57BL\/6J mice at 25 and 100 mg\/kg body weight for 10 weeks. Both peptides dose-dependently alleviated HFD-induced body weight gain, visceral fat accumulation, hepatic steatosis, dyslipidemia, hyperglycemia, and systemic inflammation. Mechanistically, both peptides inhibited intestinal PL and CE activities and enhanced fecal lipid excretion, supporting direct suppression of intestinal fat digestion. 16S rRNA gene sequencing revealed partial restoration of HFD-disrupted gut microbiota, with APAM preferentially enriching Bifidobacterium and Roseburia, while RLPA promoted Akkermansia and Lactobacillus, accompanied by differential improvements in fecal short-chain fatty acid (SCFA) profiles. Hepatic transcriptomics identified the PPAR signaling pathway as a shared regulatory hub, and multi-omics integration revealed significant correlations linking gut microbiota, SCFA production, hepatic gene expression, and metabolic phenotypes. These findings suggest a dual-pathway anti-obesity mechanism integrating intestinal lipid digestion inhibition with gut\u2013liver axis modulation, and highlight hemp seed protein-derived peptides as potential functional food ingredients for obesity prevention.<\/jats:p>","DOI":"10.3390\/foods15112040","type":"journal-article","created":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T14:10:42Z","timestamp":1780668642000},"page":"2040","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Hemp Seed Protein-Derived Lipase Inhibitory Peptides Attenuate High-Fat Diet-Induced Obesity: Evidence from Intestinal Fat Digestion and Gut\u2013Liver Axis Regulation"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9334-6937","authenticated-orcid":false,"given":"Hao","family":"Yin","sequence":"first","affiliation":[{"name":"Department of Food Science & Technology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"},{"name":"Yunnan Dali Research Institute of Shanghai Jiao Tong University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7659-6175","authenticated-orcid":false,"given":"Jiangxiong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Food Science & Technology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruilong","family":"Luo","sequence":"additional","affiliation":[{"name":"Eryuan County Inspection and Testing Institute, Dali 671299, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Food Science & Technology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhao","sequence":"additional","affiliation":[{"name":"Yunnan Dali Research Institute of Shanghai Jiao Tong University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minyan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Eryuan County Inspection and Testing Institute, Dali 671299, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0647-3151","authenticated-orcid":false,"given":"Yun","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Food Science & Technology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China"},{"name":"Yunnan Dali Research Institute of Shanghai Jiao Tong University, Dali 671000, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"107427","DOI":"10.1016\/j.fbio.2025.107427","article-title":"Rice protein-derived hypoglycemic peptides IQP, VEP and IPQ alleviate obesity-related metabolic disorders in high-fat diet (HFD)-induced C57BL\/6J mice through activation of AMPK and modulation of gut microbiota and related metabolites","volume":"72","author":"Liu","year":"2025","journal-title":"Food Biosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"773","DOI":"10.1002\/jsfa.70301","article-title":"Corn peptides alleviate high-fat diet-induced obesity and metabolic disorders in mice by regulating adipogenesis and intestinal microbial disorders","volume":"106","author":"Feng","year":"2026","journal-title":"J. Sci. Food Agric."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"109791","DOI":"10.1016\/j.jnutbio.2024.109791","article-title":"Oral administration of PIISVYWK and FSVVPSPK peptides attenuates obesity, oxidative stress, and inflammation in high fat diet-induced obese mice","volume":"136","author":"Suryaningtyas","year":"2025","journal-title":"J. Nutr. Biochem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"270","DOI":"10.1592\/phco.20.4.270.34882","article-title":"Orlistat, a new lipase inhibitor for the management of obesity","volume":"20","author":"Heck","year":"2000","journal-title":"Pharmacotherapy"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105908","DOI":"10.1016\/j.jff.2023.105908","article-title":"Novel peptides attenuate weight gain, insulin resistance, and lipid levels in mice fed a high-fat diet","volume":"112","author":"Liu","year":"2024","journal-title":"J. Funct. Foods"},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Silv\u00e9rio, R., Barth, R., Heimann, A.S., Reckziegel, P., dos Santos, G.J., Romero-Zerbo, S.Y., Berm\u00fadez-Silva, F.J., Rafacho, A., and Ferro, E.S. (2022). Pep19 has a positive effect on insulin sensitivity and ameliorates both hepatic and adipose tissue phenotype of diet-induced obese mice. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23084082"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"879","DOI":"10.1016\/j.drudis.2007.07.024","article-title":"Pancreatic lipase inhibitors from natural sources: Unexplored potential","volume":"12","author":"Birari","year":"2007","journal-title":"Drug Discov. Today"},{"key":"ref_8","first-page":"S12","article-title":"Mode of action of orlistat","volume":"21","author":"Guerciolini","year":"1997","journal-title":"Int. J. Obes."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"103529","DOI":"10.1016\/j.fbio.2023.103529","article-title":"Modulation of lipid metabolism by oyster peptides in mice with high-fat diet-induced obesity","volume":"58","author":"Chen","year":"2024","journal-title":"Food Biosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"101981","DOI":"10.1016\/j.fbio.2022.101981","article-title":"Lipid-lowering effect of microencapsulated peptides from brewer\u2019s spent grain in high-sucrose diet-fed rats","volume":"49","author":"Ferreira","year":"2022","journal-title":"Food Biosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1038\/nature05414","article-title":"An obesity-associated gut microbiome with increased capacity for energy harvest","volume":"444","author":"Turnbaugh","year":"2006","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Baek, G.H., Yoo, K.M., Kim, S.Y., Lee, D.H., Chung, H., Jung, S.C., Park, S.K., and Kim, J.S. (2023). Collagen peptide exerts an anti-obesity effect by influencing the Firmicutes\/Bacteroidetes ratio in the gut. Nutrients, 15.","DOI":"10.3390\/nu15112610"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"6454","DOI":"10.1002\/jsfa.14360","article-title":"Walnut-derived peptides combined with intermittent fasting alleviated obesity by modulating gut microbiota and liver metabolome in high-fat-diet-induced obesity mice","volume":"105","author":"Li","year":"2025","journal-title":"J. Sci. Food Agric."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Li, L., Wang, S., Zhang, T., Lv, B.J., Jin, Y.L., Wang, Y., Chen, X.J., Li, N., Han, N.P., and Wu, Y.Y. (2023). Walnut peptide alleviates obesity, inflammation and dyslipidemia in mice fed a high-fat diet by modulating the intestinal flora and metabolites. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1305656"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2325","DOI":"10.1194\/jlr.R036012","article-title":"The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism","volume":"54","author":"Groen","year":"2013","journal-title":"J. Lipid Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2200597","DOI":"10.1002\/mnfr.202200597","article-title":"Butyrate attenuates hepatic steatosis induced by a high-fat and fiber-deficient diet via the hepatic GPR41\/43-CaMKII\/HDAC1-CREB pathway","volume":"67","author":"Zheng","year":"2023","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2300258","DOI":"10.1002\/mnfr.202300258","article-title":"Quinoa peptides alleviate obesity in mice induced by a high-fat diet via regulating of the ppar-a Signaling pathway and gut microbiota","volume":"67","author":"Li","year":"2023","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"108717","DOI":"10.1016\/j.fbio.2026.108717","article-title":"Sturgeon peptide LLLE alleviates permethrin-induced obesity by modulating gut microbiota and liver transcriptome in high-fat diet-fed mice","volume":"79","author":"Chen","year":"2026","journal-title":"Food Biosci."},{"key":"ref_19","first-page":"114","article-title":"Insights into rapid identification, screening and activity investigation of novel hemp seed pancreatic lipase\/cholesterol esterase inhibitory peptides","volume":"46","author":"Yin","year":"2025","journal-title":"Sci. Technol. Food Ind."},{"key":"ref_20","first-page":"38","article-title":"Molecular Mechanism of Targeted Inhibition of Pancreatic Lipase and Cholesterol Esterase by Hempseed Peptides","volume":"46","author":"Yin","year":"2025","journal-title":"Food Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"107173","DOI":"10.1016\/j.fbio.2025.107173","article-title":"Development of alginate\/inulin-based Oral Superabsorbent Hydrogel carrier systems for delivery of white hyacinth bean polysaccharide: Improvement of characteristics and weight management in diet-induced obese mice","volume":"71","author":"Zou","year":"2025","journal-title":"Food Biosci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"9250497","DOI":"10.26599\/FSHW.2025.9250497","article-title":"Bioactive potential of black garlic melanoidins: Impact of storage conditions on digestibility and prebiotic activity","volume":"15","author":"Zhu","year":"2026","journal-title":"Food Sci. Hum. Wellness"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"108206","DOI":"10.1016\/j.fbio.2025.108206","article-title":"Steam-exploded okara ameliorates hepatic lipid metabolism in high-fat diet-induced obese C57BL\/6J mice: Evidence from multi-omics characterization","volume":"76","author":"Wen","year":"2026","journal-title":"Food Biosci."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Mao, B.Y., Ren, B.J., Wu, J.Y., Tang, X., Zhang, Q.X., Zhao, J.X., Zhang, L., Chen, W., and Cui, S.M. (2023). The Protective Effect of Broccoli Seed Extract against Lipopolysaccharide-Induced Acute Liver Injury via Gut Microbiota Modulation and Sulforaphane Production in Mice. Foods, 12.","DOI":"10.3390\/foods12142786"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Sang, X., Xing, Z.B., Zhou, B.Q., Wang, Y.T., Guan, X., Wang, F.Y., Li, Y., Zhao, Q.C., and Li, Z.B. (2025). Sea cucumber polysaccharides promote gut-liver axis health by modulating microbiota, metabolism, and gene expression in mice. Foods, 14.","DOI":"10.3390\/foods14172962"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e85","DOI":"10.1002\/imt2.85","article-title":"OmicStudio: A composable bioinformatics cloud platform with real-time feedback that can generate high-quality graphs for publication","volume":"2","author":"Lyu","year":"2023","journal-title":"iMeta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e70013","DOI":"10.1111\/boc.70013","article-title":"In toto adipocytes analysis using hydrophilic tissue clearing, light sheet microscopy, and deep learning-based image processing","volume":"117","author":"Harb","year":"2025","journal-title":"Biol. Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"9066","DOI":"10.1073\/pnas.1219451110","article-title":"Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity","volume":"110","author":"Everard","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nm.4236","article-title":"A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice","volume":"23","author":"Plovier","year":"2017","journal-title":"Nat. Med."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1021\/acs.jafc.9b06817","article-title":"Beneficial effects of dietary polyphenols on high-fat diet-induced obesity linking with modulation of gut microbiota","volume":"68","author":"Liu","year":"2020","journal-title":"J. Agric. Food Chem."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Scheithauer, T.P.M., Rampanelli, E., Nieuwdorp, M., Vallance, B.A., Verchere, C.B., van Raalte, D.H., and Herrema, H. (2020). Gut microbiota as a trigger for metabolic inflammation in obesity and type 2 diabetes. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.571731"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"L\u00f3pez-Yoldi, M., Aranaz, P., Riezu-Boj, J.I., Gonz\u00e1lez-Salazar, I., Izco, J.M., Recalde, J.I., Gonz\u00e1lez-Navarro, C.J., and Milagro, F.I. (2025). Low-molecular-weight bovine collagen peptides reduce fat accumulation in C. elegans and ameliorate obesity-related metabolic dysfunction and microbiota diversity in C57BL\/6 male diet-induced obese mice. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26189149"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1096","DOI":"10.1038\/s41591-019-0495-2","article-title":"Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: A proof-of-concept exploratory study","volume":"25","author":"Depommier","year":"2019","journal-title":"Nat. Med."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Xu, Y., Wang, N., Tan, H.Y., Li, S., Zhang, C., and Feng, Y.B. (2020). Function of Akkermansia muciniphila in obesity: Interactions with lipid metabolism, immune response and gut systems. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.00219"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1136\/gutjnl-2022-328035","article-title":"A novel peptide protects against diet-induced obesity by suppressing appetite and modulating the gut microbiota","volume":"72","author":"Li","year":"2023","journal-title":"Gut"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1017\/S0029665120006916","article-title":"SCFA: Mechanisms and functional importance in the gut","volume":"80","author":"Marinelli","year":"2021","journal-title":"Proc. Nutr. Soc."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1111\/1462-2920.13589","article-title":"Formation of propionate and butyrate by the human colonic microbiota","volume":"19","author":"Louis","year":"2017","journal-title":"Environ. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1016\/j.cmet.2011.02.018","article-title":"The microbiome and butyrate regulate energy metabolism and autophagy in the mammalian colon","volume":"13","author":"Donohoe","year":"2011","journal-title":"Cell Metab."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e00770-17","DOI":"10.1128\/mBio.00770-17","article-title":"Microbial metabolic networks at the mucus layer lead to diet-independent butyrate and vitamin B production by intestinal symbionts","volume":"8","author":"Belzer","year":"2017","journal-title":"mBio"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s10482-018-1040-x","article-title":"Deciphering the trophic interaction between Akkermansia muciniphila and the butyrogenic gut commensal Anaerostipes caccae using a metatranscriptomic approach","volume":"111","author":"Chia","year":"2018","journal-title":"Antonie Van Leeuwenhoek"},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Rios-Covian, D., Gonz\u00e1lez, S., Nogacka, A.M., Arboleya, S., Salazar, N., Gueimonde, M., and de los Reyes-Gavil\u00e1n, C.G. (2020). An overview on fecal branched short-chain fatty acids along human life and as related with body mass index: Associated dietary and anthropometric factors. Front. Microbiol., 11.","DOI":"10.3389\/fmicb.2020.00973"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1172\/JCI6223","article-title":"Peroxisome proliferator-activated receptor \u03b1 mediates the adaptive response to fasting","volume":"103","author":"Kersten","year":"1999","journal-title":"J. Clin. Investig."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1016\/j.jhep.2014.10.039","article-title":"Molecular mechanism of PPAR\u03b1 action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease","volume":"62","author":"Pawlak","year":"2015","journal-title":"J. Hepatol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.phrs.2012.11.005","article-title":"Intestinal luminal nitrogen metabolism: Role of the gut microbiota and consequences for the host","volume":"68","author":"Davila","year":"2013","journal-title":"Pharmacol. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1007\/s13105-018-0650-0","article-title":"Diet-induced obesity and associated disorders are prevented by natural bioactive type 1 fish collagen peptides (Naticol\u00ae) treatment","volume":"74","author":"Astre","year":"2018","journal-title":"J. Physiol. Biochem."}],"container-title":["Foods"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2304-8158\/15\/11\/2040\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,5]],"date-time":"2026-06-05T14:46:48Z","timestamp":1780670808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2304-8158\/15\/11\/2040"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,5]]},"references-count":45,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["foods15112040"],"URL":"https:\/\/doi.org\/10.3390\/foods15112040","relation":{},"ISSN":["2304-8158"],"issn-type":[{"value":"2304-8158","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,5]]}}}