Role of microRNA-147 in adipose tissue macrophages during obesity

• Applicant: Dr. Mengyu Zhu, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism ; Immunology ; Cardiology, Angiology ; Cell Biology
• Term: from 2020 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 439205722

A high-carbohydrate intake raises the incidence of obesity-associated adipose tissue inflammation, aggravates atherogenic dyslipidemia, and is associated with increased mortality. Triglyceride-rich VLDL, which is frequently elevated in plasma upon the high-carbohydrate diets feeding, is the major carrier of circulating LPS in hyperlipidemia and type 2 diabetes. However, the effects of incorporation of LPS in lipoproteins (in particular, LDL and VLDL) on adipose tissue macrophages (ATMs) and adipocytes during obesity are still unclear. In atherosclerosis, excessive lipid accumulation in macrophage-derived foam cells alters their energy metabolism, which is mediated by the microRNA (miRNA)-processing enzyme Dicer. Obesity induces foam cell formation in both animal and human adipose tissue; however, how cellular energy metabolism is regulated in ATMs during obesity is unknown.My preliminary results show that carbohydrate-rich western diet (HCC) aggravated obesity-associated adipose tissue inflammation in Ldlr–/– mice. Consumption of HCC facilitated hyperlipidemia-related endotoxemia characterized by elevated circulating VLDL and endotoxin concentrations. MiR-147 was selectively upregulated by HCC diet in ATMs. Deletion of Mir147 in myeloid cells altered energy metabolism of bone marrow-derived macrophages. I hypothesize that consumption of a carbohydrate-rich, western-type diet promotes the internalization of LPS-rich lipoproteins by adipose tissue, which leads to the inflammatory activation and mitochondrial dysfunction of ATMs, and thus increases adipose tissue inflammation and obesity. I believe that LPS-induced miR-147 expression in ATMs counter-regulates the phenotypic shift by regulating the energy metabolism, thus improving the function of ATMs and attenuating adipose tissue inflammation.To test this hypothesis, I will determine the effect of hyperlipidemia-related endotoxemia on miR-147 expression and adipose tissue inflammation by blocking LPS using a neutralizing antibody. To study whether HCC increased delivery of LPS-rich lipoproteins into adipose tissue, I will determine the distribution of diet-derived LPS using the isotopic tracer method. To study whether macrophage miR-147 is responsible for the diet-induced-metabolic disorders, I will investigate the effect of myeloid cell-specific knockout of Mir147 on ATMs and adipocyte function during obesity. Moreover, I will determine the role of macrophage Mir147 deficiency in energy metabolism and mitochondrial function of ATMs and adipose tissue. Next, I will study the targets of miR-147 in ATMs during obesity by co-immunoprecipitation with tAgo 2 and subsequent RNA sequencing. In addition, to assess the role of miR147-target(s) interaction in ATMs during obesity, I will specifically block the binding of miR-147 to its target(s) in diet-induced obese mice by administration of target site blockers.

• DFG Programme: Research Grants