PYY (3-36) protects against high fat feeding induced changes of pancreatic islet and intestinal hormone content and morphometry

• Published in: Biochimica et biophysica acta. General subjects 2023-06, Vol.1867 (6), p.130359-130359, Article 130359
• Main Authors: Sridhar, A., Khan, D., Flatt, P.R., Irwin, N., Moffett, R.C.
• Format: Article
• Language: English
• Subjects: Animals; apoptosis; Enteroendocrine cell; food intake; Gastrointestinal Hormones - metabolism; Gastrointestinal Hormones - pharmacology; Glucagon; glucagon-like peptide 1; Glucagon-Like Peptide 1 - metabolism; Glucagon-Like Peptide 1 - pharmacology; glucose; high fat diet; High fat diet (HFD); Ileum; immune response; Insulin-Secreting Cells - metabolism; Islet; Islets of Langerhans; Mice; morphometry; NPY2 receptor; obesity; PYY(3–36); somatostatin
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2023.130359

Prolonged high fat feeding negatively impacts pancreatic and intestinal morphology. In this regard, direct effects of PYY(3–36) on intestinal cell and pancreatic islet morphometry are yet to be fully explored in the setting of obesity. We examined the influence of 21-days twice daily treatment with PYY(3–36) on these parameters in mice fed a high fat diet (HFD). PYY(3–36) treatment decreased food intake, body weight and circulating glucose in HFD mice. In terms of intestinal morphology, crypt depth was restored to control levels by PYY(3–36), with an additional enlargement of villi length. PYY(3–36) also reversed HFD-induced decreases of ileal PYY, and especially GLP-1, content. HFD increased numbers of PYY and GIP positive ileal cells, with PYY(3–36) fully reversing the effect on PYY cell detection. There were no obvious differences in the overall number of GLP-1 positive ileal cells in all mice, barring PYY(3–36) marginally decreasing GLP-1 villi cell immunoreactivity. Within pancreatic islets, PYY(3–36) significantly decreased alpha-cell area, whilst islet, beta-, PYY- and delta-cell areas remained unchanged. However, PYY(3–36) increased the percentage of beta-cells while also reducing percentage alpha-cell area. This was related to PYY(3-36)-induced reductions of beta-cell proliferation and apoptosis frequencies. Co-localisation of islet PYY with glucagon or somatostatin was elevated by PYY(3–36), with GLP-1/glucagon co-visualisation increased when compared to lean controls. PYY(3–36) exerts protective effects on pancreatic and intestinal morphology in HFD mice linked to elevated ileal GLP-1 content. These observations highlight mechanisms linked to the metabolic and weight reducing benefits of PYY(3–36). •PYY(3–36) is a gut-derived NPY2 agonist with suggested promise for obesity therapy.•The impact of PYY(3–36) on enteroendocrine cellular adaptations in obesity is largely unknown.•We explored the effects of 21 days treatment with PYY(3–36) in high fat fed mice.•PYY(3–36) administration substantially augmented ileal GLP-1 content in HFD mice.•PYY(3–36) treatment also improved pancreatic islet morphology and beta-cell turnover.