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TNF/TNFR1 is a Key Regulator of Prolonged Fasting-Induced Decrease in Adipose Tissue.

Amanda Carla Clemente de Oliveira1,2,3, Adma Maciel Babêtto1,2, Mariele Lino Silva1,2

  • 1Immunometabolism, Department of Nutrition, Nursing School, Federal University of Minas Gerais, Belo Horizonte, Brazil.

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
|January 9, 2026
PubMed
Summary

The Tumor Necrosis Factor (TNF) and its receptor TNFR1 are essential for fat loss during fasting. Blocking TNF prevents adiposity reduction, highlighting the TNF/TNFR1 pathway

Keywords:
Interleukin‐18adipose tissuebariatric surgeryprolonged fastingtumor necrosis factor

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Area of Science:

  • Metabolic adaptation
  • Adipose tissue biology
  • Inflammation and immunity

Background:

  • Nutrient availability impacts white adipose tissue (WAT) inflammation and adiposity.
  • Tumor necrosis factor (TNF) is elevated in WAT under varying nutrient conditions.
  • The role of TNF and IL-18 in adiposity reduction during low energy availability is unclear.

Purpose of the Study:

  • To investigate the role of TNF/TNFR1 signaling in fasting-induced adiposity reduction.
  • To determine the involvement of IL-18 in fat pad loss during fasting.
  • To assess the translational relevance of these findings in human obesity.

Main Methods:

  • Utilized wild-type (WT), TNFR1 knockout, and IL-18 knockout mice.
  • Administered fasting protocols (24h and 48h) and a β3-adrenergic receptor agonist (CL316,243).
  • Analyzed subcutaneous WAT (sWAT) samples from 53 patients with obesity.

Main Results:

  • TNFR1 knockout mice were resistant to fat pad loss after fasting and agonist treatment.
  • TNF inhibition via infliximab also led to resistance to fasting-induced adiposity loss.
  • IL-18 knockout mice responded similarly to WT mice during fasting, suggesting IL-18 is not critical for fat pad loss.
  • In human sWAT, TNFR1 and IL-18 expression correlated with lipases and adipokines, but not with body weight post-bariatric surgery.

Conclusions:

  • The TNF/TNFR1 axis is critical for metabolic adaptation and fasting-induced lipolysis in male mice.
  • Prolonged fasting-induced TNF signaling is a prerequisite for adipose tissue reduction.
  • The TNF/TNFR1 pathway may have translational relevance in human obesity, particularly concerning metabolic adaptation.