HILPDA uncouples lipid storage in adipose tissue macrophages from inflammation and metabolic dysregulation

• Published in: bioRxiv
• Main Authors: Xanthe Amh Van Dierendonck, Montserrat A De La Rosa Rodriguez, Georgiadi, Anastasia, Mattijssen, Frits, Dijk, Wieneke, Michel Van Weeghel, Singh, Rajat, Borst, Jan Willem, Stienstra, Rinke, Kersten, Sander
• Format: Paper
• Language: English
• Published: Cold Spring Harbor Cold Spring Harbor Laboratory Press 05.03.2019
• Subjects: Adipose tissue; Bone marrow; Clonal deletion; Cytokines; Explants; Fatty acids; Gene expression; Glucose tolerance; Immunological tolerance; Inflammation; Intracellular levels; Lipids; Lipolysis; Macrophages; Metabolism; Obesity; Oxidative metabolism; Triglycerides
• DOI: 10.1101/566802

Obesity leads to a state of chronic low-grade inflammation that features the accumulation of lipid laden macrophages in adipose tissue. Here, we determined the role of lipid accumulation in macrophages in the development of obesity-induced adipose tissue inflammation and associated metabolic disturbances via modulation of the Hilpda gene. Hilpda was identified in a screen for obesity-induced genes in adipose tissue macrophages that are also upregulated by lipid loading. For further studies we used mice with myeloid-specific deletion of Hilpda (HilpdaΔMΦ), together with littermate controls (Hilpdaflox/flox). Deficiency of Hilpda in bone marrow-derived macrophages markedly reduced the intracellular levels of triglycerides and other major lipid species, as well as the accumulation of fluorescently-labeled fatty acids into lipid droplets, while fatty acid uptake remained unaffected. The elevated lipid storage in Hilpda-deficient macrophages could be almost completely abolished by inhibition of ATGL and was associated with a marked increase in oxidative metabolism. In diet-induced obese mice, Hilpda deficiency, despite markedly reducing lipid storage in adipose tissue macrophages, did not alter cytokine release by adipose tissue macrophages, the percentage of various immune cells in adipose tissue, inflammatory gene expression in adipose tissue, and cytokine release by adipose tissue explants. In addition, glucose tolerance and other metabolic parameters were not affected. We conclude that HILPDA is a lipid-induced physiological inhibitor of ATGL-mediated lipolysis in macrophages. In obesity, HILPDA uncouples lipid storage in adipose tissue macrophages from inflammation and metabolic dysregulation. Overall, our data question the importance of excessive lipid storage in adipose tissue macrophages in obesity-induced inflammation and metabolic dysregulation.