Endocrine Abstracts

Background: Obesity is a complex metabolic disease characterised by excess adipose tissue, that increases the risk of comorbidities such as type II diabetes. Interventions that rearrange the gut architecture or exclude nutrients from the duodenum promote immediate and long-term anti-diabetic effects, placing the gut front and centre in obesity and diabetes pathology and treatment. Currently, little is known about the pathological changes which occur in the small intestine (SI) in obesity. This study aims to determine the transcriptional signatures of each small intestinal segment and how obesity may pathologically alter these footprints.

Methods: RNA sequencing followed by differential gene expression (DE) analysis was performed on the three SI segments of mice that were fed a 60% high fat diet (DIO) (n = 10) and a chow diet (CTL) (n = 10) for 13 weeks. Standard physiological tests, such as a glucose tolerance test, confirmed the mice as metabolically obese at 13 weeks (p <0.05).

Results: Principal component analysis using the top 200 DE genes revealed distinct transcriptional footprints for each intestinal segment. In response to diet induced obesity, the duodenal signature shifts to more closely resemble the transcriptional landscape of the jejunum. Additionally, the jejunum exhibited the greatest number of DE genes in obese mice followed by the duodenum and ileum respectively. Finally, gene set enrichment analysis revealed that multiple significantly enriched pathways (p <0.1) that defined the difference between lean duodenum and jejunum, such as the adipocytokine signalling pathway, fatty acid metabolism and interferon alpha/gamma response, were no longer significant in obesity.

Conclusion: Altogether, this suggests that the obese duodenum may undergo transcriptional changes that cause it to more closely resemble the jejunum. Further analysis, such as leading-edge analysis, may identify specific gene sets that could enable us to gain a better understanding of underlying mechanisms of obesity.