Obesity-associated intracellular metabolites impact metabolic homeostasis via tissue macrophages

• Applicant: Wei He, Ph.D.
• Subject Area: Immunology ; Biochemistry
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 545573972

Obesity is a worldwide pandemic, and it is a major risk factor for multiple metabolic complications, including type II diabetes (T2D), non-alcoholic fatty liver disease and atherosclerosis. The immune system, in particular, macrophages critically contribute to the progression of obesity and its complications, thereby providing a promising call for macrophage-directed novel therapies. A metabolically activated state (Me) of macrophages induced by combined high concentrations of glucose, palmitate and insulin was recently reported to mimic obesity-associated macrophages in vitro. Benefited from our advantage in deciphering macrophage metabolism, we discovered accumulation of itaconate, mesaconate, succinate, serine, glycine and proline in mouse Me macrophages, and observed secretion of itaconate from these cells. We further confirmed accumulation of itaconate, succinate, serine and glycine in adipose tissue macrophages of diet-induced obese mice. Exogenous application of these metabolites except proline exhibited a general anti-inflammatory effect in Me macrophages, and application of itaconate/mesaconate reduced IL-6 and TNF expression in adipocytes. Fascinated by these preliminary results and our latest study highlighting the immunomodulatory effects of itaconate and mesaconate, we are intrigued to study the roles of these metabolites in macrophages during obesity. In this proposed project, we will investigate the molecular mechanism underlying Me activation-associated accumulation of itaconate, mesaconate, succinate, serine and glycine in macrophages (Aim 1), characterize the metabolite accumulation in tissue macrophages of fat and liver during obesity (Aim 2) and discover how these metabolites affect macrophage metabolism and functions in the context of obesity (Aim 3). Afterwards, we will reveal these metabolites-initiated intercellular crosstalk between macrophages and adipocytes/hepatocytes (Aim 4). Expectable, this study will not only deliver scientific significance, but also provide a vital basis for the development of novel dietary/pharmaceutical intervention in obesity and its associated complications.

• DFG Programme: Research Grants