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

FASEB J. 2021 Jul;35(7):e21665. doi: 10.1096/fj.202100543RR.


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-αFlox/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-αF/F low-fat diet (TNF-αF/F LFD), TNF-αF/F,LyzMCre LFD, TNF-αF/F HFD, or TNF-αF/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.

Keywords: TNF-α; insulin resistance; macrophage; metabolism; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diet, High-Fat
  • Female
  • Inflammation / etiology
  • Inflammation / metabolism
  • Inflammation / pathology*
  • Insulin Resistance*
  • Macrophages / metabolism*
  • Male
  • Metabolic Syndrome / etiology
  • Metabolic Syndrome / metabolism
  • Metabolic Syndrome / pathology*
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / complications*
  • Tumor Necrosis Factor-alpha / physiology*


  • Tumor Necrosis Factor-alpha