Hostname: page-component-89b8bd64d-5bvrz Total loading time: 0 Render date: 2026-05-08T21:32:16.825Z Has data issue: false hasContentIssue false
  • English
  • Français

Glucagon-like peptide-1 responses to carbohydrate, fat and protein in rats during the development of diet-induced obesity and the role of the distal small intestine

Published online by Cambridge University Press:  28 July 2025

Anri Sano ,
Satomi Tanaka ,
Kurumi Yanagihara ,
Yasuko Sakihama  and
Tohru Hira Open the ORCID record for Tohru Hira [Opens in a new window]
Anri Sano
Affiliation:
Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
Satomi Tanaka
Affiliation:
Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
Kurumi Yanagihara
Affiliation:
Graduate School of Agriculture, Hokkaido University, Sapporo, Japan
Yasuko Sakihama
Affiliation:
Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
Tohru Hira*
Affiliation:
Graduate School of Agriculture, Hokkaido University, Sapporo, Japan Research Faculty of Agriculture, Hokkaido University, Sapporo, Japan
*
Corresponding author: Tohru Hira; Email: hira@eis.hokudai.ac.jp
Get access Rights & Permissions [Opens in a new window]

Abstract

The secretion of glucagon-like peptide-1 (GLP-1) is stimulated by luminal nutrients after meal ingestion. Diet-induced obesity (DIO) may affect nutrient-induced GLP-1 secretion in humans and rodent models. We previously demonstrated that mixed meal-induced GLP-1 secretion is enhanced in rats with DIO compared with normal rats. However, it is unclear to which nutrient the GLP-1 secretion is adaptively enhanced or reduced during the development of DIO. The present study investigated the effect of obesity on the GLP-1 secretion to individual nutrients and further on GLP-1 secretory functions of the proximal and distal small intestine in rats. Male Sprague-Dawley rats were fed a control diet or a high-fat diet with sucrose solution (HFS) for 4–5 weeks. GLP-1 responses to a single oral administration of a liquid diet, dextrin, soyabean oil or whey protein were examined after 4 weeks of dietary intervention. In addition, a liquid diet was administered to the proximal or distal small intestine of anaesthetised rats (control or HFS), and GLP-1 levels in the portal vein plasma were measured. In HFS-fed rats, GLP-1 secretion to dextrin, soyabean oil and whey protein slightly increased compared with those in normal rats. Furthermore, the GLP-1 response to liquid diet administration into the lumen was greater in the distal, but not proximal, small intestine of HFS-fed rats than that in control rats. In rats with DIO, GLP-1 secretion increased, regardless of the type of nutrient. Furthermore, the distal small intestine is responsible for adaptive enhancement of the GLP-1 secretion.

Keywords

GLP-1NutrientsDiet-induced obesityIleum

Information

Type
Research Article
Information
British Journal of Nutrition , Volume 134 , Issue 3 , 14 August 2025 , pp. 186 - 194
Check for updates
Copyright
© The Author(s), 2025. Published by Cambridge University Press on behalf of The Nutrition Society

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Article purchase

Temporarily unavailable

References

Müller, TD, Finan, B, Bloom, SR, et al. (2019) Glucagon-like peptide 1 (GLP-1). Mol Metab 30, 72–130.CrossRefGoogle ScholarPubMed
Gribble, FM & Reimann, F (2021) Metabolic messengers: glucagon-like peptide 1. Nat Metab 3, 142–148.CrossRefGoogle ScholarPubMed
Holst, JJ (2024) GLP-1 physiology in obesity and development of incretin-based drugs for chronic weight management. Nat Metab 6, 1866–1885.CrossRefGoogle ScholarPubMed
Hjørne, AP, Modvig, IM & Holst, JJ (2022) The sensory mechanisms of nutrient-induced GLP-1 secretion. Metabolites 12, 420.CrossRefGoogle ScholarPubMed
Toft-Nielsen, MB, Damholt, MB, Madsbad, S, et al. (2001) Determinants of the impaired secretion of glucagon-like peptide-1 in type 2 diabetic patients. J Clin Endocrinol Metab 86, 3717–3723.CrossRefGoogle ScholarPubMed
Færch, K, Torekov, SS, Vistisen, D, et al. (2015) GLP-1 response to oral glucose is reduced in prediabetes, screen-detected type 2 diabetes, and obesity and influenced by sex: the ADDITION-PRO study. Diabetes 64, 2513–2525.CrossRefGoogle ScholarPubMed
Nauck, MA, Vardarli, I, Deacon, CF, et al. (2011) Secretion of glucagon-like peptide-1 (GLP-1) in type 2 diabetes: what is up, what is down? Diabetologia 54, 10–18.CrossRefGoogle ScholarPubMed
Watkins, JD, Carter, S, Atkinson, G, et al. (2023) Glucagon-like peptide-1 secretion in people with versus without type 2 diabetes: a systematic review and meta-analysis of cross-sectional studies. Metab 140, 155375.CrossRefGoogle ScholarPubMed
Nauck, MA & Müller, TD (2023) Incretin hormones and type 2 diabetes. Diabetologia 66, 1780–1795.CrossRefGoogle ScholarPubMed
Anini, Y & Brubaker, PL (2003) Role of leptin in the regulation of glucagon-like peptide-1 secretion. Diabetes 52, 252–259.CrossRefGoogle ScholarPubMed
Gniuli, D, Calcagno, A, Dalla Libera, L, et al. (2010) High-fat feeding stimulates endocrine, glucose-dependent insulinotropic polypeptide (GIP)-expressing cell hyperplasia in the duodenum of Wistar rats. Diabetologia 53, 2233–2240.CrossRefGoogle ScholarPubMed
Richards, P, Pais, R, Habib, AM, et al. (2016) High fat diet impairs the function of glucagon-like peptide-1 producing L-cells. Pept 77, 21–27.CrossRefGoogle ScholarPubMed
Paulsen, SJ, Larsen, LK, Hansen, G, et al. (2014) Expression of the fatty acid receptor GPR120 in the gut of diet-induced-obese rats and its role in GLP-1 secretion. PLoS One 9, e88227.CrossRefGoogle ScholarPubMed
Hunt, JE, Holst, JJ & Jepsen, SL (2022) Glucose- and bile acid-stimulated secretion of gut hormones in the isolated perfused intestine is not impaired in diet-induced obese mice. Front Endocrinol 13, 884501.CrossRefGoogle Scholar
Wang, F, Yoder, SM, Yang, Q, et al. (2015) Chronic high-fat feeding increases GIP and GLP-1 secretion without altering body weight. Am J Physiol Gastrointest Liver Physiol 309, G807–815.CrossRefGoogle ScholarPubMed
Dusaulcy, R, Handgraaf, S, Skarupelova, S, et al. (2016) Functional and molecular adaptations of enteroendocrine L-cells in male obese mice are associated with preservation of pancreatic α-cell function and prevention of hyperglycemia. Endocrinol 157, 3832–3843.CrossRefGoogle ScholarPubMed
Nakajima, S, Hira, T & Hara, H (2015) Postprandial glucagon-like peptide-1 secretion is increased during the progression of glucose intolerance and obesity in high-fat/high-sucrose diet-fed rats. Br J Nutr 113, 1477–1488.CrossRefGoogle ScholarPubMed
Hira, T, Pinyo, J & Hara, H (2020) What Is GLP-1 really doing in obesity? Trends Endocrinol Metab 31, 71–80.CrossRefGoogle ScholarPubMed
Huber, H, Schieren, A, Holst, JJ, et al. (2024) Dietary impact on fasting and stimulated GLP-1 secretion in different metabolic conditions - a narrative review. Am J Clin Nutr 119, 599–627.CrossRefGoogle ScholarPubMed
Pinyo, J, Hira, T & Hara, H (2019) Continuous feeding of a combined high-fat and high-sucrose diet, rather than an individual high-fat or high-sucrose diet, rapidly enhances the glucagon-like peptide-1 secretory response to meal ingestion in diet-induced obese rats. Nutr 62, 122–130.CrossRefGoogle ScholarPubMed
Pinyo, J, Hira, T & Hara, H (2019) Enhanced postprandial glucagon-like peptide-1 secretion during obesity development has a protective role against glucose intolerance induction in rats. Br J Nutr 122, 411–422.CrossRefGoogle Scholar
Pinyo, J, Hara, H & Hira, T (2021) Diet-induced obesity enhances postprandial glucagon-like peptide-1 secretion in Wistar rats, but not in diabetic Goto-Kakizaki rats. Br J Nutr 126, 518–530.CrossRefGoogle ScholarPubMed
Maekawa, R, Ogata, H, Murase, M, et al. (2018) Glucose-dependent insulinotropic polypeptide is required for moderate high-fat diet- but not high-carbohydrate diet-induced weight gain. Am J Physiol Endocrinol Metab 314, E572–E583.CrossRefGoogle Scholar
Seino, Y & Yamazaki, Y (2022) Roles of glucose-dependent insulinotropic polypeptide in diet-induced obesity. J Diabetes Investig 13, 1122–1128.CrossRefGoogle ScholarPubMed
Kanemaru, Y, Harada, N, Shimazu-Kuwahara, S, et al. (2020) Absence of GIP secretion alleviates age-related obesity and insulin resistance. J Endocrinol 245, 13–20.CrossRefGoogle ScholarPubMed
Miyawaki, K, Yamada, Y, Ban, N, et al. (2002) Inhibition of gastric inhibitory polypeptide signaling prevents obesity. Nat Med 8, 738–742.CrossRefGoogle ScholarPubMed
Holst, JJ & Rosenkilde, MM (2020) GIP as a therapeutic target in diabetes and obesity: insight from incretin co-agonists. J Clin Endocrinol Metab 105, e2710–2716.CrossRefGoogle ScholarPubMed
Reeves, PG (1997) Components of the AIN-93 diets as improvements in the AIN-76A diet. J Nutr 127, 838S–841S.CrossRefGoogle ScholarPubMed
Gil-Lozano, M, Wu, WK, Martchenko, A, et al. (2016) High-fat diet and palmitate alter the rhythmic secretion of glucagon-like peptide-1 by the rodent L-cell. Endocrinol 157, 586–599.CrossRefGoogle ScholarPubMed
Igarashi, A, Ogasawara, S, Takagi, R, et al. (2021) Acute oral calcium suppresses food intake through enhanced peptide-YY secretion mediated by the calcium-sensing receptor in rats. J Nutr 151, 1320–1328.CrossRefGoogle ScholarPubMed
Cani, PD, Hoste, S, Guiot, Y, et al. (2007) Dietary non-digestible carbohydrates promote L-cell differentiation in the proximal colon of rats. Br J Nutr 98, 32–37.CrossRefGoogle ScholarPubMed
Svendsen, B, Pedersen, J, Albrechtsen, NJ, et al. (2015) An analysis of cosecretion and coexpression of gut hormones from male rat proximal and distal small intestine. Endocrinol 156, 847–857.CrossRefGoogle ScholarPubMed
Mao, J, Hu, X, Xiao, Y, et al. (2013) Overnutrition stimulates intestinal epithelium proliferation through β-catenin signaling in obese mice. Diabetes 62, 3736–3746.CrossRefGoogle ScholarPubMed
Dailey, MJ (2014) Nutrient-induced intestinal adaption and its effect in obesity. Physiol Behav 136, 74–78.CrossRefGoogle ScholarPubMed
Stojanović, O, Altirriba, J, Rigo, D, et al. (2021) Dietary excess regulates absorption and surface of gut epithelium through intestinal PPARα. Nat Commun 12, 7031.CrossRefGoogle ScholarPubMed
Aranias, T, Grosfeld, A, Poitou, C, et al. (2015) Lipid-rich diet enhances L-cell density in obese subjects and in mice through improved L-cell differentiation. J Nutr Sci 4, e22.CrossRefGoogle ScholarPubMed
Supplementary material: File

Sano et al. supplementary material

Sano et al. supplementary material
Download Sano et al. supplementary material(File)
File 127.3 KB