Macrophage tumor necrosis factor‐alpha deletion does not protect against obesity‐associated metabolic dysfunction

Abstract

Abstract The pro‐inflammatory cytokine, tumor necrosis factor‐alpha (TNF‐α), has been suggested to be a key factor in the induction of obesity‐associated metabolic dysfunction. However, the role that macrophage‐derived TNF‐α has on regulating metabolic perturbations in obesity is not completely understood. Therefore, we utilized the TNF‐α Flox/Flox (F/F) , LyzMcre ± mouse model to determine the impact that macrophage TNF‐α deletion has on the development of high‐fat diet (HFD)‐induced obesity. At 10 weeks of age, male littermates were randomly assigned to 1 of 4 groups: TNF‐α F/F low‐fat diet (TNF‐α F/F LFD), TNF‐α F/F, LyzMCre LFD, TNF‐α F/F HFD, or TNF‐α F/F, LyzMCre HFD (n = 16‐28/group) and were fed their respective diets for 18 weeks. Body weight was assessed throughout the course of the experiment. Body composition, hepatic lipid accumulation, and metabolic outcomes were also examined. A microarray gene expression experiment was performed from RNA isolated from epididymal adipose tissue of the HFD‐fed groups (n = 10/group) and results were verified via qRT‐PCR for all groups. Macrophage‐derived TNF‐α deletion significantly reduced adipose tissue TNF‐α gene expression and circulating TNF‐α and downregulated genes linked to the toll‐like receptor (TLR) and NFκB signaling pathways. However, macrophage TNF‐α deletion had no effect on hindering the development of obesity, hepatic lipid accumulation, or improving glucose metabolism or insulin sensitivity. In conclusion, macrophage‐derived TNF‐α is not a causative factor for the induction of obesity‐associated metabolic dysfunction.

Topics & Concepts