Roux-en-Y Gastric Bypass and Caloric Restriction but Not Gut Hormone-Based Treatments Profoundly Impact the Hypothalamic Transcriptome in Obese Rats.

Ulrich Dischinger,Martin Fassnacht,Florian Seyfried,Christoph Otto,Julia Hasinger,Mohammed Khair Hankir,Malina Königsrainer,Tobias Heckel,Angelika Schmitt-Böhrer,Thorsten Bischler

doi:10.3390/nu14010116

Ulrich Dischinger, Martin Fassnacht + Show 8 more

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https://doi.org/10.3390/nu14010116

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Journal: Nutrients	Publication Date: Dec 28, 2021
Citations: 5	License type: CC BY 4.0

Affiliation: University Hospital Würzburg, University of Würzburg

Abstract

Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1 mg/kg/day), liraglutide s.c. (0.4 mg/kg/day), PYY3-36 + liraglutide, and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA sequencing. Results: While rats in the RYGB, BWM, and PYY3-36 + liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt, and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36 + liraglutide-, liraglutide-, and PYY-treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36 + liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.

Highlights

Obesity currently affects more than one-third of the global population and represents a major socioeconomic burden [1,2,3]
Looking for similar differences in Roux-en-Y gastric bypass (RYGB) and body weight-matched (BWM) groups compared with the sham group, we identified an upregulation of the leptin receptor (Lepr) and its mediating pathways, such as the JAK–STAT, the PI3K–Akt, and the AMPK pathway (Figure 4)
Using a hypothesis-free RNA sequencing method, we found that only RYGB and BWM rats induced relevant differences in hypothalamic mRNA expression compared with controls

Summary

Introduction

Obesity currently affects more than one-third of the global population and represents a major socioeconomic burden [1,2,3]. Available noninvasive treatment options for severe obesity lack efficacy and result in long-term weight regain in the vast majority of patients. We have recently shown that a combinatory treatment ofPYY3-36 and the stable GLP-1 analogue liraglutide leads to similar changes in body weight compared to RYGB in diet-induced obese rats [35]. Both therapies proved to be effective in reducing overall food intake and high-fat preference [35]. Further underlining the relevance of PYY3-36 and GLP-1, we could increase high-fat food preference of RYGB-treated rats by using antagonists of their respective receptors [36]

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