Deregulation of lysosomal and mitochondrial dynamics in obesity

In recent years, it is increasingly recognized that changes in cellular nutrient status impact organelle dynamics. Yet, the physiological relevance thereof as well as the inherent tissue-specific mechanisms remain enigmatic. Research described in this thesis aims at unravelling hitherto undefined signalling pathways in white adipose tissue (WAT) that are (de)regulated in obesity, with emphasis on the core hallmarks of insulin resistance (IR), namely low-grade inflammation and mitochondrial dysfunction. A holistic approach, involving bioinformatics, genetic, and pharmacological strategies in cultured cells and murine obesity models is used to identify novel transcriptional circuits that modulate organelle dynamics in WAT and resident adipose tissue macrophages (ATMs). We describe a regulatory circuit in which peroxisome proliferator–activated receptor γ (PPARγ), the adipocyte master regulator and receptor for the thiazolidinedione (TZD) class of antidiabetic drugs, controls mitochondrial network fragmentation through transcriptional induction of the BH3-only Bnip3. This mode of action leads to adipose insulin sensitization and improved mitochondrial bioenergetics. Additionally, we report the activation of a coherent lysosomal gene program in obese ATMs, governed by the MiT/TFE family of transcription factors. Altogether, these data uncover transcriptionally regulated organelle dynamics in adipose tissue, and its (de)regulation in obesity-related IR.