Effects of liraglutide plus PYY3-36 vs. Roux-en-Y gastric bypass on hypothalamic gene expression

Background Central effects of Roux-en-Y gastric bypass (RYGB) are highly suggestive, but still not entirely elucidated. Additionally, it is unclear, if they are cause or consequence of the pronounced weight loss. To further clarify this, we compared the effects of RYGB and a chronic systemic administration of glucagon-like peptide-1 (GLP-1) and peptide tyrosine tyrosine 3-36 (PYY3-36) on hypothalamic gene expression in a standardized experimental setting.

Methods High-fat diet-induced obese male Wistar rats were randomized into six groups: RYGB, sham-operation, liraglutide, PYY3-36, PYY3-36+liraglutide, saline. Animals were kept on a free choice high- and low-fat diet. Food intake, preference and body weight were measured daily for 4 weeks. Open field (OF) and elevated plus maze (EPM) tests were performed. RNA sequencing and qPCR were performed with hypothalamic mRNA.

Results RYGB and combined PYY3-36+liraglutide treatment led to a similar and plateaued weight loss and also reduced overall food intake and (less pronounced) high-fat preference compared to controls. The animals showed no signs of abnormal behavior in OF or EPM. RYGB led to a vast amount of upregulated genes and pathways in the hypothalamus, particularly the leptin receptor and its mediating pathways PI3K-Akt and JAK-STAT. By contrast, no relevant changes could be detected in PYY3-36+liraglutide, liraglutide and PYY treated animals.

Conclusions While RYGB leads to pronounced hypothalamic changes, this is not the case for PYY3-36+liraglutide treated animals with a similar body weight course. This underlines the potential of RYGB as a “neurosurgical” intervention and might be the cause of the durability of its effectivity.

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Publication History

Article published online:
06 May 2021