Metformin targets intestinal immune system signaling pathways in a high-fat diet-induced mouse model of obesity and insulin resistance.

Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101555782 Publication Model: eCollection Cited Medium: Print ISSN: 1664-2392 (Print) Linking ISSN: 16642392 NLM ISO Abbreviation: Front Endocrinol (Lausanne) Subsets: MEDLINE

Original Publication: [Lausanne : Frontiers Research Foundation]

Metformin*/pharmacology ; Metformin*/therapeutic use ; Insulin Resistance*; Male ; Animals ; Mice ; Female ; Diet, High-Fat/adverse effects ; NF-kappa B/metabolism ; Mice, Inbred C57BL ; Obesity/drug therapy ; Obesity/metabolism ; Insulin/therapeutic use ; Disease Models, Animal ; Immune System/metabolism ; Signal Transduction ; Immunoglobulins

Introduction: Research findings of the past decade have highlighted the gut as the main site of action of the oral antihyperglycemic agent metformin despite its pharmacological role in the liver. Extensive evidence supports metformin's modulatory effect on the composition and function of gut microbiota, nevertheless, the underlying mechanisms of the host responses remain elusive. Our study aimed to evaluate metformin-induced alterations in the intestinal transcriptome profiles at different metabolic states.
Methods: The high-fat diet-induced mouse model of obesity and insulin resistance of both sexes was developed in a randomized block experiment and bulk RNA-Seq of the ileum tissue was the method of choice for comparative transcriptional profiling after metformin intervention for ten weeks.
Results: We found a prominent transcriptional effect of the diet itself with comparatively fewer genes responding to metformin intervention. The overrepresentation of immune-related genes was observed, including pronounced metformin-induced upregulation of immunoglobulin heavy-chain variable region coding Ighv1-7 gene in both high-fat diet and control diet-fed animals. Moreover, we provide evidence of the downregulation NF-kappa B signaling pathway in the small intestine of both obese and insulin-resistant animals as well as control animals after metformin treatment. Finally, our data pinpoint the gut microbiota as a crucial component in the metformin-mediated downregulation of NF-kappa B signaling evidenced by a positive correlation between the Rel and Rela gene expression levels and abundances of Parabacteroides distasonis , Bacteroides spp ., and Lactobacillus spp . in the gut microbiota of the same animals.
Discussion: Our study supports the immunomodulatory effect of metformin in the ileum of obese and insulin-resistant C57BL/6N mice contributed by intestinal immunoglobulin responses, with a prominent emphasis on the downregulation of NF-kappa B signaling pathway, associated with alterations in the composition of the gut microbiome.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2023 Brīvība, Silamiķele, Kalniņa, Silamiķelis, Birzniece, Ansone, Jagare, Elbere and Kloviņš.)

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Keywords: NF-kappa B signaling; high-fat diet; humoral immune responses; intestinal transcriptome; metformin

9100L32L2N (Metformin)
0 (NF-kappa B)
0 (Insulin)
0 (Immunoglobulins)

Date Created: 20231005 Date Completed: 20231102 Latest Revision: 20231109

20240628

PMC10546317

10.3389/fendo.2023.1232143

37795356