Adipose tissue macrophages promote myelopoiesis and monocytosis in obesity

Cell Metab. 2014 May 6;19(5):821-35. doi: 10.1016/j.cmet.2014.03.029.

Abstract

Obesity is associated with infiltration of macrophages into adipose tissue (AT), contributing to insulin resistance and diabetes. However, relatively little is known regarding the origin of AT macrophages (ATMs). We discovered that murine models of obesity have prominent monocytosis and neutrophilia, associated with proliferation and expansion of bone marrow (BM) myeloid progenitors. AT transplantation conferred myeloid progenitor proliferation in lean recipients, while weight loss in both mice and humans (via gastric bypass) was associated with a reversal of monocytosis and neutrophilia. Adipose S100A8/A9 induced ATM TLR4/MyD88 and NLRP3 inflammasome-dependent IL-1β production. IL-1β interacted with the IL-1 receptor on BM myeloid progenitors to stimulate the production of monocytes and neutrophils. These studies uncover a positive feedback loop between ATMs and BM myeloid progenitors and suggest that inhibition of TLR4 ligands or the NLRP3-IL-1β signaling axis could reduce AT inflammation and insulin resistance in obesity.

Publication types

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

MeSH terms

  • Adipose Tissue / metabolism*
  • Animals
  • Bone Marrow / metabolism
  • Carrier Proteins / metabolism
  • Cell Proliferation / physiology
  • Humans
  • Inflammasomes / metabolism
  • Interleukin-1beta / metabolism
  • Macrophages / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / metabolism*
  • Myeloid Differentiation Factor 88 / metabolism
  • Myelopoiesis / physiology*
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neutrophils / metabolism
  • Obesity / metabolism*
  • Receptors, Interleukin-1 / metabolism
  • Toll-Like Receptor 4 / metabolism

Substances

  • Carrier Proteins
  • Inflammasomes
  • Interleukin-1beta
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • Receptors, Interleukin-1
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4