Elucidating the role of gut hormones in infertility associated with diabetes, obesity and PCOS

Abstract

Obesity poses an enormous threat to life expectancy and quality of life in people with associated metabolic comorbidities. Alongside its metabolic implications, obesity and associated diabetes impair female reproductive function, causing infertility and PCOS. This thesis focuses on modifications during obesity, diabetes and related infertility with an emphasis on gut and pancreatic hormone distribution. Current observations suggest a therapeutic role for gut hormones in infertility/PCOS associated with metabolic pathophysiology.

High-fat diet (HFD) induced obese rat and mice exhibited significant impairments in estrous cycling followed by altered levels of reproductive hormones in circulation that manifested in disturbed ovarian morphology. Gene expression of INSR and GLP-1Rs were upregulated in the ovaries and adrenals. In the intestine, HFD caused significant decreases in ileal crypt depth and villi length. Moreover, cell densities of GIP, GLP-1 and PYY in the ileum increased after HFD in rodents while their secretory capacity decreased. HFD also caused islet cell hyperplasia and increased beta cell apoptosis. Roux-en-Y gastric bypass (RYGB) surgery reduced crypt depths in the alimentary limb (AL) and biliopancreatic limb (BPL) of rats with no significant changes in ileal morphology. RYGB also reversed L-cell hyperplasia and increased their secretory capacity in the ileum. In the AL, RYGB increased GLP-2 cell density. In islets, RYGB reduced alpha cell area and reduced beta cell apoptosis. This was subsequent to decreases in co-localisation of PYY and GLP-1 with glucagon while PYY co-localisation increased in delta cells. Mice treated with Ex-4 and PYY(3-36) increased crypt depth and villi length while significantly decreasing PYY positive cells in the ileum. mGIP(3-30) had similar effects on villi length and PYY positive cells. All three peptides restored and increased L-cell GLP-1 secretory capacity initially impaired by HFD. Within islets, PYY(3-36) and mGIP(3-30) xi increased the percentage of beta cells while decreasing alpha cell percentage. Ex- 4 was able to reduce the percentage of central alpha cells after HFD. These peptides also increased co-localisation of PYY with glucagon and somatostatin. PYY(3-36) was able to reduce beta cell proliferation and apoptosis in HFD mice. Oral administration of medium and high dose ethinyl estradiol (EE2) increased villi length in the ileum while low and high dose EE2 decreased GLP-1 and PYY cells. However, GLP-1 and PYY content increased significantly after high and medium dose EE2 respectively. In islets, medium dose EE2 decreased alpha cell area and consequently increased co- localization of GLP-1 with glucagon. High dose EE2 increased beta cell proliferation while decreasing beta cell apoptosis. Taken together, the present thesis unravels a domain of research focusing on the developmental mechanisms of obesity-related infertility and the role of key gut hormones as treatment alternatives for diet-induced fertility disorders.

Date of Award	Mar 2023
Original language	English
Supervisor	Charlotte Moffett (Supervisor), Dawood Khan (Supervisor) & Peter Flatt (Supervisor)