Lysosomal stress in obese adipose tissue macrophages contributes to MITF-dependent GPNMB induction
- Tanit L. Gabriel1,
- Marc J. Tol1,
- Roelof Ottenhof1,
- Cindy van Roomen1,
- Jan Aten2,
- Nike Claessen2,
- Berend Hooibrink3,
- Barbara de Weijer4,
- Mireille J. Serlie4,
- Carmen Argmann5,
- Leonie van Elsenburg1,
- Johannes M.F.G. Aerts1 and
- Marco van Eijk1,*
- Departments of 1Medical Biochemistry,
- 3Cell Biology and
- 4Endocrinology and Metabolism, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
- 5Genetics and Genomic Sciences Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
- *Corresponding author: Dr. M. van Eijk, E-mail:
In obesity, adipose tissue contains crown-like structures where macrophages surround non-viable adipocytes. To understand how adipose tissue macrophages (ATM) contribute to development of insulin resistance we examined their character in more detail.
In silico analysis of F2 mouse populations revealed significant correlation between adipose glycoprotein non-metastatic melanoma protein B (Gpnmb) expression and body weight. In obese mice and individuals Gpnmb expression was induced in ATM. Cultured RAW264.7 cells were used to obtain insight into the mechanism of Gpnmb regulation. Gpnmb was potently induced by lysosomal stress inducers including palmitate and chloroquine, or Torin1, an inhibitor of mammalian target of rapamycin complex (mTORC)1. These stimuli also provoked MITF translocation to the nucleus and knockdown of MITF by shRNA indicated its absolute requirement for Gpnmb induction. In agreement with our in vitro data, reduced mTORC1 activity was observed in isolated ATMs from obese mice, which coincided with increased nuclear MITF localisation and Gpnmb transcription.
Aberrant nutrient sensing provokes lysosomal stress, resulting in attenuated mTORC1 activity -and enhanced MITF-dependent Gpnmb induction. Our data identify Gpnmb as a novel marker for obesity-induced ATM infiltration, and potentiator of IL-4 responses and point towards a crucial role for MITF in driving part of the adipose tissue macrophage phenotype.
- Received November 9, 2013.
- Accepted April 21, 2014.
- © 2014 by the American Diabetes Association.
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