Lysosomal stress in obese adipose tissue macrophages contributes to MITF-dependent Gpnmb induction.

In obesity, adipose tissue (AT) contains crown-like structures where macrophages surround nonviable adipocytes. To understand how AT macrophages (ATMs) 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 nonmetastatic melanoma protein B (Gpnmb) expression and body weight. In obese mice and obese individuals, Gpnmb expression was induced in ATMs. 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 1 (mTORC1). These stimuli also provoked microphthalmia transcription factor (MITF) translocation to the nucleus, and knockdown of MITF by short hairpin RNA 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 localization 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 interleukin-4 responses and point toward a crucial role for MITF in driving part of the ATM phenotype.