Ellagic Acid and Urolithins A and B Differentially Regulate Fat Accumulation and Inflammation in 3T3-L1 Adipocytes While Not Affecting Adipogenesis and Insulin Sensitivity

Abstract

Ellagic acid (EA) is a component of ellagitannins, present in crops such as pecans, walnuts, and many berries, which metabolized by the gut microbiota forms urolithins A, B, C, or D. In this study, ellagic acid, as well as urolithins A and B, were tested on 3T3-L1 preadipocytes for differentiation and lipid accumulation. In addition, inflammation was studied in mature adipocytes challenged with lipopolysaccharide (LPS). Results indicated that EA and urolithins A and B did not affect differentiation (adipogenesis) and only EA and urolithin A attenuated lipid accumulation (lipogenesis), which seemed to be through gene regulation of glucose transporter type 4 (GLUT4) and adiponectin. On the other hand, gene expression of cytokines and proteins associated with the inflammation process indicate that urolithins and EA differentially inhibit tumor necrosis factor alpha (TNFα), inducible nitric oxide synthase (iNOS), interleukin 6 (IL-6), and monocyte chemoattractant protein-1 (MCP-1). Urolithins A and B were found to reduce nuclear levels of phosphorylated nuclear factor κB (p-NF-κB), whereas all treatments showed expression of nuclear phosphorylated protein kinase B (p-AKT) in challenged LPS cells when treated with insulin, indicating the fact that adipocytes remained insulin sensitive. In general, urolithin A is a compound able to reduce lipid accumulation, without affecting the protein expression of peroxisome proliferator-activated receptor-γ (PPARγ), CCAAT/enhancer binding protein-α (c/EBPα), and PPARα, whereas EA and urolithin B were found to enhance PPARγ and c/EBPα protein expressions as well as fatty acid (FA) oxidation, and differentially affected lipid accumulation. individuals (metabotype 0), as well as urolithin producer individuals metabotypes A (mainly urolithin A derivatives) or metabotype B (mainly urolithin B and A derivatives). Differences in intestinal microbiota have been associated with the interindividual variability, which seems also correlated with health status and predisposition to chronic diseases (e.g., metabolic syndrome) [7].Several studies have indicated that ellagic acid and its derivative urolithins possess beneficial effects against prostate and colon cancer and exert some proestrogenic/antiestrogenic effects [8][9][10], as well as having anti-inflammatory activity in colon fibroblasts and protection against oxidative stress [11,12]. Other reports have shown antiatherogenic effects in human umbilical vein endothelial cells [13] and neuroprotective effects against Alzheimer's disease in in vitro studies [14].However, these compounds (EA and Uro) as potential anti-obesity treatments have started to acquire attention in recent years. Obesity is a complex disorder with multiple causes, including both genetic and environmental factors, and is associated with the risk of insulin resistance (type 2 diabetes), fatty liver disease, hypertension, and atherosclerosis [15].Over the past years, in vitro systems have been used to define the transcriptional events regulating preadipocyte differentiat...

Immunomodulatory Role of Urolithin A on Metabolic Diseases

“…UroA increased fatty acid oxidation through AMPK-dependent mechanisms to decrease triglyceride accumulation [ 59 ]. In 3T3-L1 murine pre-adipocytes, UroA decreased triglyceride content and abolished the expression of PPARγ, Glut4, and FABP4 in pre-adipocytes [ 60 ] and dampened lipogenesis without impairing adipogenesis [ 61 ]. Recent studies suggest UroA protects against high-fat-diet-induced obesity and related insulin resistance.…”

Modulation of the host microbiome by black raspberries or their components and the therapeutic implications in cancer

“…Studies linking ellagic acid to gut flora changes are currently limited. This is thought to be due to the fact that the majority of ellagic acid is quickly metabolized into urolithins within the gut (Cisneros‐Zevallos, Bang, & Delgadillo‐Puga, 2020; Giménez‐Bastida, Ávila‐Gálvez, Espín, & González‐Sarrías, 2020). Thus, more recent studies have focused on determining the efficacy of urolithins in the treatment of cancer and how this relates to the host microbiome (Giménez‐Bastida et al., 2020; González‐Sarrías, Tomé‐Carneiro, Bellesia, Tomás‐Barberán, & Espín, 2015).…”

Polyphenols: Potential anti‐inflammatory agents for treatment of metabolic disorders

“…In another study, pretreatment with Urolithin‐A was able to lower production of TNF‐α, iNOS, and IL‐6, reduce both NF‐кB DNA binding activity and NF‐кBp65 translocation, inhibit both c‐jun translocation and c‐jun phosphorylation, decrease Akt, JNK phosphorylation and to a lesser extent, p38 phosphorylation in LPS stimulated murine RAW264.7 macrophages (Komatsu et al, 2018). Furthermore, Urolithin A and B could downregulate TNF‐α, iNOS, IL‐6, MCP‐1, and NF‐κB expression in mature adipocytes treated with LPS (Cisneros‐Zevallos et al, 2020).…”