Receptors for Tumor Necrosis Factor-α Play a Protective Role against Obesity and Alter Adipose Tissue Macrophage Status

Abstract

TNF-alpha signals through two receptors, TNFR1 and TNFR2. Our goals were: 1) determine the role of TNFRs in obesity and metabolic disease and 2) investigate whether TNFRs contribute to the link between obesity and adipose tissue macrophage infiltration and polarization. R1(-/-)R2(-/-) (RKO) and wild-type (WT) mice were fed standard chow or a high-fat/high-sucrose diet (HFHS) over 14 wk. Body composition, food intake, and energy expenditure were measured. Oral glucose tolerance and insulin sensitivity tests assessed glucose homeostasis. Adipose tissue and systemic inflammatory status were evaluated by quantifying plasma adipokine levels and macrophage-specific gene expression in fat. RKO mice were heavier (10%) and fatter (18%) than WT controls at 4 wk of age and were 26% heavier and 50% fatter than WT after 14 wk of HFHS diet feeding. Age- and diet-adjusted 24-h oxygen consumption, activity, and respiratory exchange ratio were significantly reduced in RKO mice. Obese RKO mice were markedly insulin resistant, suggesting that intact TNFR signaling is not required for the effect of obesity to impair glucose metabolism. Adipose tissue from HFHS-fed RKO mice exhibited increased macrophage infiltration, but compared with WT mice, macrophage phenotypic markers featured a predominance of antiinflammatory M2 over proinflammatory M1 cells. TNFRs play a physiological role to limit body weight and adiposity by modestly increasing metabolic rate and fatty acid oxidation, and they are required for obesity-induced activation of adipose tissue macrophages. Despite these effects, TNFRs are not required for obesity-induced insulin resistance.

Deficiency of lymphotoxin-α does not exacerbate high-fat diet-induced obesity but does enhance inflammation in mice

“…All procedures were done in accordance with current National Institutes of Health (NIH) guidelines and approved by the Animal Care and Use Committee of the University of Washington. Results for the WT mice were reported previously in a separate analysis of obesity and TNFR-deficient mice (53). Results for our LT Ϫ/Ϫ mice were obtained in simultaneous feeding studies with the WT and TNFR Ϫ/Ϫ mouse studies, but results for the test strains are being published separately due to the large quantity of data and separate types of findings.…”

“…Since TNF and its receptors have clearly been shown to modulate obesity (23,53) and insulin resistance (71), we hypothesize that LT, by virtue of being a ligand for TNFRs, is also an obesity modifier. Since mice lacking TNF are protected from diet-induced obesity (22,71), we suggest that lack of LT (LT Ϫ/Ϫ ) results in decreased T cell lymphocyte recruitment to adipose tissue, which in turn reduces macrophage accumulation and thereby limits adipose tissue inflammation and insulin resistance.…”

Chronic TNF-α Neutralization Does Not Improve Insulin Resistance or Endothelial Function in “Healthy” Men with Metabolic Syndrome

“…There are a number of reports showing that endogenous (that is, in mice lacking TNF-α or TNF receptor) (22,23) or exogenous (TNF-α neutralization) interference with TNF-α signaling ameliorates insulin resistance during development of obesity (7,24), whereas other reports using similar strategies have failed to show an effect of TNF-α neutralization on insulin sensitivity (25,26). The reason for this discrepancy is unclear, but it may reflect dietary differences or differences in genetic backgrounds of the mice studied.…”

ABCG1 regulates mouse adipose tissue macrophage cholesterol levels and ratio of M1 to M2 cells in obesity and caloric restriction

“…WT mice fed the HFD have been repeatedly shown to gain body weight and fat, accompanied by systemic and adipose tissue infl ammation ( 11,14,15,43,46,51,58 ). What is not known is whether alterations in myeloidderived Abcg1 Ϫ / Ϫ worsen obesity or alter the course of body weight and fat loss during caloric restriction.…”