Endocrine Abstracts

Background: An activation of the hypothalamic-pituitary-adrenal (HPA) axis is a common observation in obese individuals. GLP-1 agonists, such as semaglutide, and SGLT-2 inhibitors, such as empagliflozin, are well known to be beneficial in obesity, while other incretins, like peptide tyrosine tyrosine 3-36 (PYY 3-36), might be also useful for the treatment of obesity. However, the effect of these substances on the adrenal gland is largely unknown. We directly compared the effects of semaglutide alone and in combination with PYY as well as empagliflozin alone and in combination with semaglutide on adrenal gland transcriptomics.

Methods: High-fat diet (HFD)-induced obese male Wistar rats (n=50; mean bodyweight 260g) were randomized into the following treatment groups: semaglutide, semaglutide+PYY3-36, empagliflozin, semaglutide+empagliflozin, and saline. Animals had free access to high- and low-fat diet. After an observation period of 8 weeks, adrenal glands were taken out and evaluated using hypothesis-free RNA sequencing.

Results: Semaglutide and more pronounced semaglutide+PYY3-36 treatment led to weight loss, reduced overall food intake and (less pronounced) high-fat preference compared to saline treated controls. Empagliflozin had only mild effects on body weight. Interestingly, semaglutide+PYY3-36 treatment (compared to saline) led to a high amount of significantly upregulated genes (n=320) in the adrenal glands, which was much less pronounced in semaglutide and/or empagliflozin treated animals. Pathway analysis revealed a high number of activated pathways, most prominent among them: PI3K-Akt signaling, insulin signaling, renin-angiotensin system, neuroactive ligand-receptor interaction, adrenergic signalling.

Conclusions: Semaglutide+PYY3-36 combination therapy induces strong changes of adrenal gland transcriptome. Further analyses are necessary to identify exact mechanisms of GLP-1 and PYY based therapies on adrenal gland functionality, potentially leading to new treatment options for adrenal pathologies and for obesity related hypercortisolism.