AS: Conceptualization, Data curation, Formal analysis, Writing—original draft, Writing—review & editing, Investigation. VNI: Data curation, Formal analysis, Writing—original draft. OM: Data curation, Formal analysis. PRF: Conceptualization, Supervision, Visualization, Writing—review & editing. CRM: Conceptualization, Funding acquisition, Supervision, Visualization, Writing—review & editing. DK: Conceptualization, Data curation, Supervision, Visualization, Writing—review & editing. All authors read and approved the submitted version.
Conflicts of interest
Dr. Dawood Khan, who is the Guest Editor of Exploration of Endocrine and Metabolic Diseases, had no involvement in the decision-making or the review process of this manuscript. The other authors declare no conflicts of interest.
Ethical approval
All experiments were conducted under the UK Animals (Scientific Procedures) Act 1986 & EU Directive 2010/63EU as well as the UK Home Office animal project license number PPL2902, and approved by the University of Ulster Animal Welfare and Ethical Review Body (AWERB).
Consent to participate
Not applicable.
Consent to publication
Not applicable.
Availability of data and materials
The datasets supporting the findings of this study are available from the corresponding author upon reasonable request.
Funding
These studies were supported by Diabetes UK RD Lawrence Fellowship grant to RCM and Ulster University strategic funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.
References
Grant B, Sandelson M, Agyemang-Prempeh B, Zalin A. Managing obesity in people with type 2 diabetes.Clin Med. 2021;21:e327–231. [DOI] [PubMed] [PMC]
Farhadipour M, Depoortere I. The Function of Gastrointestinal Hormones in Obesity—Implications for the Regulation of Energy Intake.Nutrients. 2021;13:1839. [DOI] [PubMed] [PMC]
Varghese M, Griffin C, Abrishami S, Eter L, Lanzetta N, Hak L, et al. Sex hormones regulate metainflammation in diet-induced obesity in mice.J Biol Chem. 2021;297:101229. [DOI] [PubMed] [PMC]
Varghese M, Griffin C, Singer K. The Role of Sex and Sex Hormones in Regulating Obesity-Induced Inflammation.Adv Exp Med Biol. 2017;1043:65–86. [DOI] [PubMed]
Freeman EW, Sammel MD, Lin H, Gracia CR. Obesity and reproductive hormone levels in the transition to menopause.Menopause. 2010;17:718–26. [DOI] [PubMed] [PMC]
Alemany M. Estrogens and the regulation of glucose metabolism.World J Diabetes. 2021;12:1622–54. [DOI] [PubMed] [PMC]
Gupte AA, Pownall HJ, Hamilton DJ. Estrogen: An Emerging Regulator of Insulin Action and Mitochondrial Function.J Diabetes Res. 2015;2015:916585. [DOI] [PubMed] [PMC]
Vigil P, Meléndez J, Petkovic G, Del Río JP. The importance of estradiol for body weight regulation in women.Front Endocrinol. 2022;13:951186. [DOI] [PubMed] [PMC]
Drel VR, Mashtalir N, Ilnytska O, Lyzogubov VV, Li F, Shin J, et al. Leptin‐deficient (ob/ob) mouse‐ a new animal model of peripheral neuropathy of Type 2 diabetes and obesity.FASEB J. 2007;21:e21. [DOI]
Everard A, Lazarevic V, Derrien M, Girard M, Muccioli GG, Neyrinck AM, et al. Responses of Gut Microbiota and Glucose and Lipid Metabolism to Prebiotics in Genetic Obese and Diet-Induced Leptin-Resistant Mice.Diabetes. 2011;60:2775–86. [DOI] [PubMed] [PMC]
Suriano F, Vieira-Silva S, Falony G, Roumain M, Paquot A, Pelicaen R, et al. Novel insights into the genetically obese (ob/ob) and diabetic (db/db) mice: two sides of the same coin.Microbiome. 2021;9:147. [DOI] [PubMed] [PMC]
Kanno A, Asahara SI, Masuda K, Matsuda T, Kimura-Koyanagi M, Seino S, et al. Compensatory hyperinsulinemia in high-fat diet-induced obese mice is associated with enhanced insulin translation in islets.Biochem Biophys Res Commun. 2015;458:681–6. [DOI] [PubMed]
Sridhar A, Khan D, Flatt PR, Irwin N, Moffett RC. PYY (3–36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry.Biochim Biophys Acta Gen Subj. 2023;1867:130359. [DOI] [PubMed]
Kellard JA, Rorsman NJG, Hill TG, Armour SL, van de Bunt M, Rorsman P, et al. Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high-fat diet.Mol Metab. 2020;40:101021. [DOI] [PubMed] [PMC]
Pepin É, Al-Mass A, Attané C, Zhang K, Lamontagne J, Lussier R, et al. Pancreatic β-Cell Dysfunction in Diet-Induced Obese Mice: Roles of AMP-Kinase, Protein Kinase Cε, Mitochondrial and Cholesterol Metabolism, and Alterations in Gene Expression.PLOS ONE. 2016;11:e0153017. [DOI] [PubMed] [PMC]
Liu S, Le May C, Wong WP, Ward RD, Clegg DJ, Marcelli M, et al. Importance of Extranuclear Estrogen Receptor-α and Membrane G Protein-Coupled Estrogen Receptor in Pancreatic Islet Survival.Diabetes. 2009;58:2292–302. [DOI] [PubMed] [PMC]
Tiano JP, Delghingaro-Augusto V, Le May C, Liu S, Kaw MK, Khuder SS, et al. Estrogen receptor activation reduces lipid synthesis in pancreatic islets and prevents β cell failure in rodent models of type 2 diabetes.J Clin Investig. 2011;121:3331–42. [DOI] [PubMed] [PMC]
Ma W, Chen X, Cerne R, Syed SK, Ficorilli JV, Cabrera O, et al. Catechol estrogens stimulate insulin secretion in pancreatic β-cells via activation of the transient receptor potential A1 (TRPA1) channel.J Biol Chem. 2019;294:2935–46. [DOI] [PubMed] [PMC]
Le May C, Chu K, Hu M, Ortega CS, Simpson ER, Korach KS, et al. Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice.Proc Natl Acad Sci. 2006;103:9232–7. [DOI] [PubMed] [PMC]
Kooptiwut S, Mahawong P, Hanchang W, Semprasert N, Kaewin S, Limjindaporn T, et al. Estrogen reduces endoplasmic reticulum stress to protect against glucotoxicity induced-pancreatic β-cell death.J Steroid Biochem Mol Biol. 2014;139:25–32. [DOI] [PubMed]
Yamabe N, Kang KS, Zhu BT. Beneficial effect of 17β-estradiol on hyperglycemia and islet β-cell functions in a streptozotocin-induced diabetic rat model.Toxicol Appl Pharmacol. 2010;249:76–85. [DOI] [PubMed]
Wu T, Xu J, Xu S, Wu L, Zhu Y, Li G, et al. 17β-Estradiol Promotes Islet Cell Proliferation in a Partial Pancreatectomy Mouse Model.J Endocr Soc. 2017;1:965–79. [DOI] [PubMed] [PMC]
JavanMoghadam S, Weihua Z, Hunt KK, Keyomarsi K. Estrogen receptor alpha is cell cycle-regulated and regulates the cell cycle in a ligand-dependent fashion.Cell Cycle. 2016;15:1579–90. [DOI] [PubMed] [PMC]
Sridhar A, Khan D, Flatt PR, Moffett CR, Irwin N. GLP-1 receptor agonism and GIP receptor antagonism induce substantial alterations in enteroendocrine and islet cell populations in obese high fat fed mice.Peptides. 2023;169:171093. [DOI] [PubMed]
Xue Y, Wang H, Du M, Zhu MJ. Maternal obesity induces gut inflammation and impairs gut epithelial barrier function in nonobese diabetic mice.J Nutr Biochem. 2014;25:758–64. [DOI] [PubMed] [PMC]
Stearns AT, Balakrishnan A, Rhoads DB, Tavakkolizadeh A. Rapid Upregulation of Sodium-Glucose Transporter SGLT1 in Response to Intestinal Sweet Taste Stimulation.Ann Surg. 2010;251:865–71. [DOI] [PubMed] [PMC]
Nguyen NQ, Debreceni TL, Bambrick JE, Chia B, Wishart J, Deane AM, et al. Accelerated Intestinal Glucose Absorption in Morbidly Obese Humans: Relationship to Glucose Transporters, Incretin Hormones, and Glycemia.J Clin Endocrinol Metab. 2015;100:968–76. [DOI] [PubMed]
Zubiaga L, Vilallonga R, Ruiz-Tovar J, Torres A, Pattou F. Importance of the Gastrointestinal Tract in Type 2 Diabetes. Metabolic Surgery Is More Than Just Incretin Effect.Cir Esp (Engl Ed). 2018;96:537–45. [DOI]
Nie X, Xie R, Tuo B. Effects of Estrogen on the Gastrointestinal Tract.Dig Dis Sci. 2018;63:583–96. [DOI] [PubMed]
Handgraaf S, Dusaulcy R, Visentin F, Philippe J, Gosmain Y. 17-β Estradiol regulates proglucagon-derived peptide secretion in mouse and human α- and L cells.JCI Insight. 2018;3:e3. [DOI] [PubMed] [PMC]
Gribble FM, Reimann F. Function and mechanisms of enteroendocrine cells and gut hormones in metabolism.Nat Rev Endocrinol. 2019;15:226–37. [DOI] [PubMed]
Nwako JG, McCauley HA. Enteroendocrine cells regulate intestinal homeostasis and epithelial function.Mol Cell Endocrinol. 2024;593:112339. [DOI] [PubMed] [PMC]
Maeng LY, Beumer A. Never fear, the gut bacteria are here: Estrogen and gut microbiome-brain axis interactions in fear extinction.Int J Psychophysiol. 2023;189:66–75. [DOI] [PubMed]
Kim YH, Lee JH, Yeung JL, Das E, Kim RY, Jiang Y, et al. Thermogenesis-independent metabolic benefits conferred by isocaloric intermittent fasting in ob/ob mice.Sci Rep. 2019;9:2479. [DOI] [PubMed] [PMC]
Cheval L, Sampaio JL, Poindessous V, Crambert G, Pallet N. The lipidome of the kidney tubules of ob/ob mice is affected at the infralesional level.Cell Death Discov. 2025;11:521. [DOI] [PubMed] [PMC]
Gordon MN, Osterburg HH, May PC, Finch CE. Effective Oral Administration of 17β-Estradiol to Female C57BL/6J Mice through the Drinking Water1.Biol Reprod. 1986;35:1088–95. [DOI] [PubMed]
Khan D, Vasu S, Moffett RC, Irwin N, Flatt PR. Influence of neuropeptide Y and pancreatic polypeptide on islet function and beta-cell survival.Biochim Biophys Acta (BBA) - Gen Subj. 2017;1861:749–58. [DOI] [PubMed]
Sridhar A, Khan D, Abdelaal M, Elliott JA, Naughton V, Flatt PR, et al. Differential effects of RYGB surgery and best medical treatment for obesity-diabetes on intestinal and islet adaptations in obese-diabetic ZDSD rats.PLOS ONE. 2022;17:e0274788. [DOI] [PubMed] [PMC]
Flatt PR, Bailey CJ. Plasma Glucose and Insulin Responses to Glucagon and Arginine in Aston ob/ob Mice: Evidence for a Selective Defect in Glucose-Mediated Insulin Release.Horm Metab Res. 2008;14:127–30. [DOI] [PubMed]
Bian C, Bai B, Gao Q, Li S, Zhao Y. 17β-Estradiol Regulates Glucose Metabolism and Insulin Secretion in Rat Islet β Cells Through GPER and Akt/mTOR/GLUT2 Pathway.Front Endocrinol. 2019;10:531. [DOI] [PubMed] [PMC]
Tiano JP, Mauvais-Jarvis F. Importance of oestrogen receptors to preserve functional β-cell mass in diabetes.Nat Rev Endocrinol. 2012;8:342–51. [DOI] [PubMed]
Mauvais-Jarvis F, Clegg DJ, Hevener AL. The Role of Estrogens in Control of Energy Balance and Glucose Homeostasis.Endocr Rev. 2013;34:309–38. [DOI] [PubMed] [PMC]
Acharya KD, Gao X, Bless EP, Chen J, Tetel MJ. Estradiol and high fat diet associate with changes in gut microbiota in female ob/ob mice.Sci Rep. 2019;9:20192. [DOI] [PubMed] [PMC]
Gao H, Bryzgalova G, Hedman E, Khan A, Efendic S, Gustafsson JA, et al. Long-Term Administration of Estradiol Decreases Expression of Hepatic Lipogenic Genes and Improves Insulin Sensitivity in ob/ob Mice: A Possible Mechanism Is through Direct Regulation of Signal Transducer and Activator of Transcription 3.Mol Endocrinol. 2006;20:1287–99. [DOI] [PubMed]
Roepke TA. Oestrogen Modulates Hypothalamic Control of Energy Homeostasis Through Multiple Mechanisms.J Neuroendocrinol. 2009;21:141–50. [DOI] [PubMed] [PMC]
Ding LC, Gong QQ, Li SW, Fu XL, Jin YC, Zhang J, et al. Rcan2 and estradiol independently regulate body weight in female mice.Oncotarget. 2017;8:48098–109. [DOI] [PubMed] [PMC]
Cortés ME, Carrera B, Rioseco H, Pablo del Río J, Vigil P. The Role of Kisspeptin in the Onset of Puberty and in the Ovulatory Mechanism: A Mini-review.J Pediatr Adolesc Gynecol. 2015;28:286–91. [DOI] [PubMed]
Yan H, Yang W, Zhou F, Li X, Pan Q, Shen Z, et al. Estrogen Improves Insulin Sensitivity and Suppresses Gluconeogenesis via the Transcription Factor Foxo1.Diabetes. 2018;68:291–304. [DOI] [PubMed] [PMC]
Chen JQ, Brown TR, Russo J. Regulation of energy metabolism pathways by estrogens and estrogenic chemicals and potential implications in obesity associated with increased exposure to endocrine disruptors.Biochim Biophys Acta (BBA) - Mol Cell Res. 2009;1793:1128–43. [DOI] [PubMed] [PMC]
Nadal A, Alonso-Magdalena P, Soriano S, Ropero AB, Quesada I. The role of oestrogens in the adaptation of islets to insulin resistance.J Physiol. 2009;587:5031–7. [DOI] [PubMed] [PMC]
Ribas V, Drew BG, Zhou Z, Phun J, Kalajian NY, Soleymani T, et al. Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females.Sci Transl Med. 2016;8:334ra54. [DOI] [PubMed] [PMC]
Zhou Z, Ribas V, Rajbhandari P, Drew BG, Moore TM, Fluitt AH, et al. Estrogen receptor α protects pancreatic β-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress.J Biol Chem. 2018;293:4735–51. [DOI] [PubMed] [PMC]
Ellenbroek JH, Töns HAM, Hanegraaf MAJ, Rabelink TJ, Engelse MA, Carlotti F, et al. Pancreatic α‐cell mass in obesity.Diabetes Obes Metab. 2017;19:1810–3. [DOI] [PubMed]
Merino B, Alonso-Magdalena P, Lluesma M, Ñeco P, Gonzalez A, Marroquí L, et al. Pancreatic alpha-cells from female mice undergo morphofunctional changes during compensatory adaptations of the endocrine pancreas to diet-induced obesity.Sci Rep. 2015;5:11622. [DOI] [PubMed] [PMC]
Bru-Tari E, Cobo-Vuilleumier N, Alonso-Magdalena P, Dos Santos RS, Marroqui L, Nadal A, et al. Pancreatic alpha-cell mass in the early-onset and advanced stage of a mouse model of experimental autoimmune diabetes.Sci Rep. 2019;9:9515. [DOI] [PubMed] [PMC]
Khan D, Vasu S, Moffett RC, Irwin N, Flatt PR. Islet distribution of Peptide YY and its regulatory role in primary mouse islets and immortalised rodent and human beta-cell function and survival.Mol Cell Endocrinol. 2016;436:102–13. [DOI] [PubMed]
Sam AH, Gunner DJ, King A, Persaud SJ, Brooks L, Hostomska K, et al. Selective Ablation of Peptide YY Cells in Adult Mice Reveals Their Role in Beta Cell Survival.Gastroenterology. 2012;143:459–68. [DOI] [PubMed]
Hauge-Evans AC, King AJ, Carmignac D, Richardson CC, Robinson IC, Low MJ, et al. Somatostatin Secreted by Islet δ-Cells Fulfills Multiple Roles as a Paracrine Regulator of Islet Function.Diabetes. 2009;58:403–11. [DOI] [PubMed] [PMC]
Richards P, Pais R, Habib AM, Brighton CA, Yeo GS, Reimann F, et al. High fat diet impairs the function of glucagon-like peptide-1 producing L-cells.Peptides. 2016;77:21–7. [DOI] [PubMed] [PMC]
Soares A, Beraldi EJ, Ferreira PE, Bazotte RB, Buttow NC. Intestinal and neuronal myenteric adaptations in the small intestine induced by a high-fat diet in mice.BMC Gastroenterol. 2015;15:3. [DOI] [PubMed] [PMC]
Zheng Z, Zong Y, Ma Y, Tian Y, Pang Y, Zhang C, et al. Glucagon-like peptide-1 receptor: mechanisms and advances in therapy.Signal Transduct Target Ther. 2024;9:234. [DOI] [PubMed] [PMC]
Fukuda M. The Role of GIP Receptor in the CNS for the Pathogenesis of Obesity.Diabetes. 2021;70:1929–37. [DOI] [PubMed] [PMC]
Buchan AM, Polak JM, Capella C, Solcia E, Pearse AG. Electronimmunocytochemical evidence for the K cell localization of gastric inhibitory polypeptide (GIP) im man.Histochemistry. 1978;56:37–44. [DOI] [PubMed]
Eissele R, Göke R, Willemer S, Harthus HP, Vermeer H, Arnold R, et al. Glucagon‐like peptide‐1 cells in the gastrointestinal tract and pancreas of rat, pig and man.Eur J Clin Investig. 2008;22:283–91. [DOI] [PubMed]
Barker N. Adult intestinal stem cells: critical drivers of epithelial homeostasis and regeneration.Nat Rev Mol Cell Biol. 2013;15:19–33. [DOI] [PubMed]
Choi J, Augenlicht LH. Intestinal stem cells: guardians of homeostasis in health and aging amid environmental challenges.Exp Mol Med. 2024;56:495–500. [DOI] [PubMed] [PMC]
de Santa Barbara P, van den Brink GR, Roberts DJ. Development and differentiation of the intestinal epithelium.Cell Mol Life Sci. 2003;60:1322–32. [DOI] [PubMed] [PMC]
Cho NL, Javid SH, Carothers AM, Redston M, Bertagnolli MM. Estrogen Receptors α and β Are Inhibitory Modifiers of Apc-Dependent Tumorigenesis in the Proximal Colon of Min/+ Mice.Cancer Res. 2007;67:2366–72. [DOI] [PubMed]
Wada-Hiraike O, Imamov O, Hiraike H, Hultenby K, Schwend T, Omoto Y, et al. Role of estrogen receptor β in colonic epithelium.Proc Natl Acad Sci. 2006;103:2959–64. [DOI] [PubMed] [PMC]
Wang Q, Li Z, Liu K, Liu J, Chai S, Chen G, et al. Activation of the G Protein–Coupled Estrogen Receptor Prevented the Development of Acute Colitis by Protecting the Crypt Cell.J Pharmacol Exp Ther. 2021;376:281–93. [DOI] [PubMed]