Elsevier

Molecular Metabolism

Volume 6, Issue 10, October 2017, Pages 1226-1239
Molecular Metabolism

Original Article
Activated macrophages control human adipocyte mitochondrial bioenergetics via secreted factors

https://doi.org/10.1016/j.molmet.2017.07.008Get rights and content
Under a Creative Commons license
open access

Highlights

  • CD40:CD163 ratio in human WAT is proportional to OXPHOS expression.

  • CD40:CD163 ratio is high in LPS/IFNγ- and low in IL10/TGFβ-activated MΦs.

  • Opposing action on adipocyte bioenergetics by LPS/IFNγ- vs IL10/TGFβ-activated MΦs.

Abstract

Objective

Obesity-associated WAT inflammation is characterized by the accumulation and local activation of macrophages (MΦs), and recent data from mouse studies suggest that macrophages are modifiers of adipocyte energy metabolism and mitochondrial function. As mitochondrial dysfunction has been associated with obesity and the metabolic syndrome in humans, herein we aimed to delineate how human macrophages may affect energy metabolism of white adipocytes.

Methods

Human adipose tissue gene expression analysis for markers of macrophage activation and tissue inflammation (CD11c, CD40, CD163, CD206, CD80, MCP1, TNFα) in relationship to mitochondrial complex I (NDUFB8) and complex III (UQCRC2) was performed on subcutaneous WAT of 24 women (BMI 20–61 kg/m2). Guided by these results, the impact of secreted factors of LPS/IFNγ- and IL10/TGFβ-activated human macrophages (THP1, primary blood-derived) on mitochondrial function in human subcutaneous white adipocytes (SGBS, primary) was determined by extracellular flux analysis (Seahorse technology) and gene/protein expression.

Results

Stepwise regression analysis of human WAT gene expression data revealed that a linear combination of CD40 and CD163 was the strongest predictor for mitochondrial complex I (NDUFB8) and complex III (UQCRC2) levels, independent of BMI. IL10/TGFβ-activated MΦs displayed high CD163 and low CD40 expression and secreted factors that decreased UQCRC2 gene/protein expression and ATP-linked respiration in human white adipocytes. In contrast, LPS/IFNγ-activated MΦs showed high CD40 and low CD163 expression and secreted factors that enhanced adipocyte mitochondrial activity resulting in a total difference of 37% in ATP-linked respiration of white adipocytes (p = 0.0024) when comparing the effect of LPS/IFNγ- vs IL10/TGFβ-activated MΦs.

Conclusion

Our data demonstrate that macrophages modulate human adipocyte energy metabolism via an activation-dependent paracrine mechanism.

Keywords

Cytokines
Oxidative phosphorylation
Glycolysis
Cellular metabolism

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