The Direct and Indirect Inhibition of Proinflammatory Adipose Tissue Macrophages by Acarbose in Diet-Induced Obesity

Rheumatology and Immunology Endocrinology Cell Biology Immunology Medicine Life Sciences Biochemistry Gastroenterology Pharmacy
Acarbose Proinflammatory macrophages Obesity Gut microbiota Immune regulation Insulin resistance Inflammation

Exploring the Direct and Indirect Immunomodulatory Effects of Acarbose on Obesity-Associated Chronic Inflammation

Academic Background

With the global prevalence of obesity, related metabolic syndromes such as insulin resistance (IR), type 2 diabetes, cardiovascular diseases, and fatty liver disease have become major threats to human health. These conditions also place a significant economic burden on societies and lead to a decline in patients’ quality of life and life expectancy. An increasing body of evidence suggests that chronic low-grade inflammation associated with obesity, particularly in adipose tissue, is a key mechanism driving insulin resistance. Adipose tissue macrophages (ATMs) play a critical role in this process, transitioning from anti-inflammatory M2 phenotypes to pro-inflammatory M1 phenotypes, thereby exacerbating insulin resistance and systemic inflammation.

Additionally, the gut microbiome and its metabolites have gained widespread attention for their ability to regulate host metabolism and immune homeostasis. Obesity and metabolic disorders disrupt gut microbial homeostasis, altering the composition and metabolites of gut microbial communities, further promoting chronic inflammation. However, leveraging gut microbiota and the immune system to mitigate obesity-related diseases remains an area requiring deeper scientific exploration.

Acarbose (ACA), as an alpha-glucosidase inhibitor, is widely used to treat type 2 diabetes and metabolic disorders caused by insulin resistance. Studies have shown that, in addition to significantly reducing postprandial blood glucose and insulin levels, acarbose can regulate the composition of the gut microbiome, providing additional weight-loss and anti-inflammatory benefits for patients with obesity and diabetes. However, the precise immunomodulatory mechanisms of acarbose have yet to be fully elucidated.

Research Source

This study was conducted by Xiaohui Li, Shimeng Zheng, Dong Zhang, and their collaborators, who are affiliated with Capital Medical University and related institutions in Beijing, China. The work was published in the January 2025 issue of Cell Reports Medicine (DOI: 10.1016/j.xcrm.2024.101883). Combining animal experiments, in vitro studies, and metabolomics analyses, the researchers uncovered how acarbose regulates adipose tissue inflammation through gut microbiota and its metabolites.

Workflow of the Study

The study mainly consisted of the following experimental steps:

  1. Establishment of the Animal Model and Intervention
    The researchers used high-fat diet (HFD)-fed C57BL/6 mice for 18 weeks to establish an obesity model. Subsequently, the mice received acarbose in drinking water for 4 weeks. The study tracked and measured the mice’s body weight, food intake, glucose tolerance, insulin sensitivity, and adipose tissue morphology. Simultaneously, flow cytometry was used to analyze immune cells in adipose tissue, evaluating changes in the quantity and phenotypes of macrophages.

  2. Antibiotic Experiment to Assess Gut Microbiota’s Role
    To investigate the involvement of gut microbiota in acarbose-mediated regulation of obesity-induced inflammation, the researchers treated obese mice with an antibiotic cocktail (ABX) to deplete gut microbiota, followed by acarbose treatment. They compared the differences between microbiota-depleted and non-depleted groups, particularly in macrophage infiltration and inflammatory cytokine expression.

  3. Gut Microbiome and Metabolomics Analysis
    Using 16S rRNA sequencing of fecal samples, the study found that acarbose significantly altered the composition of the gut microbiome in obese mice, particularly by increasing the abundance of a bacterial genus Parasutterella. Metabolomic analysis of serum indicated significantly elevated short-chain fatty acid (SCFA) levels after acarbose treatment, with a particular increase in propionic acid (PA).

  4. In Vitro and In Vivo Validation Experiments
    To confirm the specific effects of propionic acid, bone marrow-derived macrophages (BMDMs) were treated with propionic acid in vitro. PA was found to significantly inhibit the survival and inflammatory cytokine secretion (e.g., TNF-α) of M1 macrophages via the GPR43 receptor. Additionally, the researchers innovatively labeled acarbose with fluorescence to provide evidence of its direct effects on macrophages in adipose tissue.

  5. Exploration of Signaling Pathways
    Through transcriptomic and protein analyses, the researchers revealed that acarbose activated the GPR120 receptor in adipose tissue macrophages. This modulation regulated the mTOR signaling pathway, enhancing lysosomal and mitochondrial functions and ultimately promoting macrophage apoptosis.

Major Findings

  1. Acarbose Significantly Improved Metabolic Indicators in Obese Mice
    Compared to mice on a high-fat diet alone, those treated with acarbose showed significantly less weight gain, lower fasting blood glucose, improved glucose tolerance, and enhanced insulin sensitivity.

  2. Acarbose Regulated Macrophage Polarization and Survival
    Acarbose treatment significantly reduced the proportion of pro-inflammatory M1 macrophages while promoting the accumulation of anti-inflammatory M2 macrophages. This was achieved by inducing apoptosis of M1 macrophages, demonstrating a direct regulatory effect of acarbose on macrophage function in obesity-associated chronic inflammation.

  3. Immune Regulation Mediated by Parasutterella and Its Metabolites
    The study revealed that increases in Parasutterella abundance driven by acarbose led to higher production of propionic acid. PA inhibited the survival of pro-inflammatory macrophages and reduced the secretion of cytokines via activation of the GPR43 receptor.

  4. Acarbose Directly Promoted Functional Switching in Macrophages
    Using innovative fluorescence-labeling technology, the researchers demonstrated that acarbose can directly act on macrophages in adipose tissue. It activated the GPR120 receptor and regulated the mTOR signaling pathway, enhancing lysosomal and mitochondrial functions to promote macrophage apoptosis.

Significance and Value of the Research

This study provides a comprehensive view of how acarbose exerts both direct and indirect immunomodulatory effects on adipose tissue inflammation, offering significant scientific insights into its use for treating obesity and insulin resistance. By uncovering how acarbose regulates gut microbiota and its metabolites to mitigate obesity-associated metabolic disturbances, the research highlights the potential of gut microbiota-host interactions for therapeutic interventions in metabolic diseases. Additionally, the innovative techniques employed, such as fluorescent labeling of acarbose, and the exploration of GPR120 and GPR43 signaling pathways, offer valuable insights for targeted therapies against metabolic inflammatory diseases.

Research Highlights

  • Demonstrated for the first time that acarbose exerts dual mechanisms—direct and indirect effects—on adipose tissue macrophages.
  • Identified the critical role of Parasutterella and its metabolite, propionic acid, in regulating obesity-associated inflammation.
  • Used an innovative technique (fluorescent labeling of acarbose) to validate its direct effects on macrophages.
  • Proposed a novel molecular mechanism through the GPR120/mTOR signaling pathway to regulate macrophage functions.

This research opens new avenues for immunotherapy strategies targeting obesity and related diseases. Its findings are expected to advance the application of gut microbiota-based therapies, with acarbose at the core, in the treatment of obesity.