Role of Hepatocyte-Derived Extracellular Vesicles in Metabolic Inflammation and Glycemic Control of Obesity
Abstract
Topic Area: Diabetes The worldwide prevalence of obesity has reached pandemic proportions. Increasing evidence indicates that obesity is a major risk factor for insulin resistance (IR) and the subsequent development of type 2 diabetes (T2D), which increases the risk of long-term complications including cardiovascular disease, stroke, and peripheral vascular disease. According to the World Health Organization, T2D will affect more than 300 million people by the year 2025. Despite enormous research efforts put forth in the study of obesity and diabetes over the past 30 years, the molecular mechanisms by which obesity leads to insulin resistance and T2D remain elusive. During the pathogenesis of obesity, significant activation and infiltration of immune cells into metabolic tissues, such as the liver and adipose tissues, lead to chronic activation of inflammatory pathways in both tissues and immune cells. This atypical state engages immune response pathways that adversely impact nutrient metabolism and insulin action. Accumulated evidence indicates blocking inflammation or the activity of inflammatory molecules benefits to the improvement of glucose metabolism in many mouse models. However, there is no successful pharmacologic treatment that directly inhibits typical inflammatory pathways for insulin resistance and T2D patients. Therapeutic development for IR and T2D may arise from a shift in our thinking about the mechanisms that underline induction and continuation of inflammation in obesity. To fill gaps in understanding of the mechanistic basis of these extensive functional links between inflammation and obesity-associated IR and T2D, we hypothesize that there exist additional pathogenic humoral factors that regulate inflammatory responses in the pathogenesis of obesity. As such, we focus on the role of microvesicles (30–1000 nm), including exosomes (30–100 nm), that are released from many cell types into the extracellular space, are distributed in body fluids, in obesity. Microvesicles/exosomes are enclosed by bilayer membranes and contains various proteins and nucleic acids, including microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). These vesicles travel to neighboring and distant organs and subsequently modulate the cellular functions within the recipient cells. Essentially, microvesicles/exosomes serve as a novel mode of intercellular communication. Additional evidence suggests that microvesicles/exosomes play a key role in pathophysiological processes, including obesity and its metabolic complications, and can serve as novel biomarkers and even therapeutic targets. In this study, we aim to critically evaluate the role of obesity-driven, hepatocyte-derived microvesicles/exosomes in the regulation of inflammation and glucose metabolism, utilizing our unique, newly established mouse model that permits monitoring of tissue-specific microvesicles/exosomes in vivo. Based on our results, we anticipate developing novel microvesicle/exosome-based therapeutic options for IR and T2D, towards reducing the burden of pandemic obese issues.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910038
Entities
People
- Takahisa Nakamura
Organizations
- Cincinnati Children's Hospital Medical Center
- United States Army