Enhanced glycolysis and HIF-1\u03b1 activation in adipose tissue macrophages sustains local and systemic interleukin-1\u03b2 production in obesity

Susan Hutchison,Graeme Koelwyn,Edward A Fisher,Ludovic Boytard,Bhama Ramkhelawon,Russell Simon,Mireille Ouimet,Monika Sharma,Westley Spiro,Lena Seifert,Bo Yan,Kathryn J Moore,Ravichandran Ramasamy,Tarik Hadi

doi:10.1038/s41598-020-62272-9

Susan Hutchison, Graeme Koelwyn + Show 12 more

Open Access

https://doi.org/10.1038/s41598-020-62272-9

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Journal: Scientific Reports	Publication Date: Mar 27, 2020
Citations: 63	License type: open-access

Affiliation: New York University Langone Medical Center

Abstract

During obesity, macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type II diabetes. Evidence suggests that the rewiring of cellular metabolism can regulate macrophage function. However, the metabolic programs that characterize adipose tissue macrophages (ATM) in obesity are poorly defined. Here, we demonstrate that ATM from obese mice exhibit metabolic profiles characterized by elevated glycolysis and oxidative phosphorylation, distinct from ATM from lean mice. Increased activation of HIF-1α in ATM of obese visceral adipose tissue resulted in induction of IL-1β and genes in the glycolytic pathway. Using a hypoxia-tracer, we show that HIF-1α nuclear translocation occurred both in hypoxic and non-hypoxic ATM suggesting that both hypoxic and pseudohypoxic stimuli activate HIF-1α and its target genes in ATM during diet-induced obesity. Exposure of macrophages to the saturated fatty acid palmitate increased glycolysis and HIF-1α expression, which culminated in IL-1β induction thereby simulating pseudohypoxia. Using mice with macrophage-specific targeted deletion of HIF-1α, we demonstrate the critical role of HIF-1α-derived from macrophages in regulating ATM accumulation, and local and systemic IL-1β production, but not in modulating systemic metabolic responses. Collectively, our data identify enhanced glycolysis and HIF-1α activation as drivers of low-grade inflammation in obesity.

Highlights

During obesity, macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type II diabetes
Recent studies indicate that rewiring of cellular energy metabolism can regulate macrophage phenotype and function, yet little is known about the metabolic programs that characterize adipose tissue macrophages (ATM) in obesity
We defined the metabolic programs engaged in adipose tissue macrophages in the context of obesity, and demonstrated that this is directly linked to their proinflammatory phenotype via the transcription factor HIF-1α

Summary

Introduction

Macrophages infiltrate the visceral adipose tissue and promote inflammation that contributes to type II diabetes. Classically activated M[LPS + IFNγ] macrophages have enhanced glycolysis that provides a rapid source of ATP from glucose to sustain their high secretory and phagocytic functions, and feeds the pentose phosphate pathway to generate amino acids for protein synthesis, ribose for nucleotides and NADPH for the production of reactive oxygen species (ROS) by NADPH oxidase[17] These metabolic programs were originally thought to merely reflect the cell’s energy substrate utilization, recent studies using chemical or genetic inhibitors of glycolysis and fatty acid oxidation have shown that disrupting these programs can alter macrophage phenotype and inflammatory functions[16,17,18]. We show that targeted deletion of HIF-1α, in myeloid cells, reduced ATM accumulation in the WAT of high fat diet fed mice, as well as local and systemic IL-1β production, implicating HIF-1α as a guardian of metabolic stress and inflammation in obesity

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