Anorexigenic and anti-inflammatory signaling pathways of semaglutide via the microbiota–gut––brain axis in obese mice

Nov 25, 2024Inflammopharmacology

How semaglutide may reduce appetite and inflammation through the gut microbiome and brain communication in obese mice

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Abstract

Mice fed a high-fat diet exhibited higher blood glucose and increased insulin resistance.

High-fat diet led to elevated levels of inflammatory markers in the gut and serum.
Treatment with semaglutide improved dyslipidemia and insulin resistance.
Semaglutide altered gut microbiome composition, increasing Bacteroidetes and promoting acetate-producing bacteria.
Increased hypothalamic acetate levels were observed following semaglutide treatment.
Semaglutide enhanced the number of hypothalamic neurons associated with appetite regulation.
The intervention reduced hypothalamic neuroinflammation and improved insulin signaling pathways.

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Our study focused on a mouse model of obesity induced by a high-fat diet (HFD). We administered Semaglutide intraperitoneally (Ozempic ®-0.05 mg/Kg-translational dose) every seven days for six weeks. HFD-fed mice had higher blood glucose, lipid profile, and insulin resistance. Moreover, mice fed HFD showed high gut levels of TLR4, NF-kB, TNF-α, IL-1β, and nitrotyrosine and low levels of occludin, indicating intestinal inflammation and permeability, culminating in higher serum levels of IL-1β and LPS. Treatment with semaglutide counteracted the dyslipidemia and insulin resistance, reducing gut and serum inflammatory markers. Structural changes in gut microbiome were determined by 16S rRNA sequencing. Semaglutide reduced the relative abundance of Firmicutes and augmented that of Bacteroidetes. Meanwhile, semaglutide dramatically changed the overall composition and promoted the growth of acetate-producing bacteria (Bacteroides acidifaciens and Blautia coccoides), increasing hypothalamic acetate levels. Semaglutide intervention increased the number of hypothalamic GLP-1R+ neurons that mediate endogenous action on feeding and energy. In addition, semaglutide treatment reversed the hypothalamic neuroinflammation HDF-induced decreasing TLR4/MyD88/NF-κB signaling and JNK and AMPK levels, improving the hypothalamic insulin resistance. Also, semaglutide modulated the intestinal microbiota, promoting the growth of acetate-producing bacteria, inducing high levels of hypothalamic acetate, and increasing GPR43+ /POMC+ neurons. In the ARC, acetate activated the GPR43 and its downstream PI3K-Akt pathway, which activates POMC neurons by repressing the FoxO-1. Thus, among the multifactorial effectors of hypothalamic energy homeostasis, possibly higher levels of acetate derived from the intestinal microbiota contribute to reducing food intake.

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Anorexigenic and anti-inflammatory signaling pathways of semaglutide via the microbiota–gut––brain axis in obese mice

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