The role of visceral adipose tissue secretome in the development of metabolic dysfunction-associated steatotic liver disease

• Applicant: Dr. Lucia Mastrototaro
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 555504551

Obesity and the presence of type 2 diabetes mellitus (T2DM) are major drivers in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). This condition involves the release of fatty acids from adipose tissue (AT) and their accumulation in the liver, leading to altered hepatic lipid metabolism. Dysfunctional AT exacerbates obesity and MASLD by releasing hormones, cytokines, and extracellular vesicles (EV). While lipid overload increases mitochondrial function in the liver, mitochondrial respiration is reduced in the visceral adipose tissue (VAT) of obese individuals with MASLD. This reduction in VAT mitochondrial respiration is associated with higher adipose tissue insulin resistance. Small EV (sEV) are essential components of interorgan crosstalk and can exacerbate lipid deposition and inflammation in hepatocytes, as well as induce insulin resistance in lean mice when derived from obese mice. In humans, the number of circulating and subcutaneous AT (SAT)-derived sEV increases with MASLD, and sEV from SAT of obese individuals with MASLD impair insulin signaling in vitro, potentially worsening T2DM and MASLD. This suggests that sEV might serve as potential biomarkers for MASLD development, and might contribute to T2DM and MASLD pathogenesis. Thus, the current study aims to investigate how sEV contribute to the development and progression of MASLD. Specifically, we want to elucidate if abnormal mitochondrial activity in VAT influences the release of sEV, which may worsen MASLD in obese individuals. The main objective is to characterize the protein cargo of VAT-derived and circulating sEV in obese individuals with and without MASLD in order to define a specific sEV signature indicative of MASLD and understand disease mechanisms by investigating the sEV-mediated crosstalk between VAT and hepatocytes. Understanding these mechanisms may provide insights into novel therapeutic strategies for managing and reducing the burden of T2DM and its associated complications, including MASLD, by manipulating the content and blocking the production of VAT-derived sEV.

• DFG Programme: Research Grants
• Co-Investigator: Dr. Kalliopi Pafili