Improved Glucose Homeostasis Following Vertical Sleeve Gastrectomy is Associated with Alternate Wiring of the Liver Molecular Clock in a Rat Model of Spontaneously-Occurring Type 2 Diabetes

Bariatric surgery is associated with remission of type 2 diabetes (T2D). We aimed to advance fundamental understanding of mechanisms involved in improved glucose homeostasis following vertical sleeve gastrectomy (VSG). We carried out a series of pathophysiological, behavioural and liver transcriptome analyses in lean rats of the Goto-Kakizaki (GK) model of polygenic T2D following VSG or sham operation. VSG and resulting sustained reduction in glucose intolerance were associated with significant changes in liver histology and lean mass, and nycthemeral feeding patterns and activity. Liver transcriptome profiling identified differentially regulated pathways between VSG and sham GK, including inflammatory and immune processes and fatty acid metabolism. Deeper analysis of the transcriptome dataset showed that expression of almost all main regulators of the molecular clock was significantly and co-ordinately affected by VSG. Comparisons with liver transcriptome data previously generated in GK and normoglycemic rats suggested that VSG results in a profound remodelling of the regulation of the molecular clock. Our findings shed light on relationships between the molecular clock and nycthemeral feeding and activity, which may contribute to long-term therapeutic consequences of VSG in the context of polygenic T2D in the absence of confounding effects of obesity. ### Competing Interest Statement The authors have declared no competing interest. * BN : Brown Norway GK : Goto-Kakizaki GSEA : Gene Set Enrichment Analysis IPGTT : Intraperitoneal Glucose Tolerance Test KEGG : Kyoto Encyclopedia of Genes and Genomes NES : Normalised Enrichment Scores OLETF : Otsuka Long-Evans Tokushima Fatty ORA : Over-Representation Analysis P.copri : Prevotella copri RYGB : Roux-en-Y gastric bypass VSG : Vertical Sleeve Gastrectomy