Mitophagy Mediates the Beige to White Transition of Human Primary Subcutaneous Adipocytes Ex Vivo

Abstract

Brown and beige adipocytes have multilocular lipid droplets, express uncoupling protein (UCP) 1, and promote energy expenditure. In rodents, when the stimulus of browning subsides, parkin-dependent mitophagy is activated and dormant beige adipocytes persist. In humans, however, the molecular events during the beige to white transition have not been studied in detail. In this study, human primary subcutaneous abdominal preadipocytes were differentiated to beige for 14 days, then either the beige culture conditions were applied for an additional 14 days or it was replaced by a white medium. Control white adipocytes were differentiated by their specific cocktail for 28 days. Peroxisome proliferator-activated receptor γ-driven beige differentiation resulted in increased mitochondrial biogenesis, UCP1 expression, fragmentation, and respiration as compared to white. Morphology, UCP1 content, mitochondrial fragmentation, and basal respiration of the adipocytes that underwent transition, along with the induction of mitophagy, were similar to control white adipocytes. However, white converted beige adipocytes had a stronger responsiveness to dibutyril-cAMP, which mimics adrenergic stimulus, than the control white ones. Gene expression patterns showed that the removal of mitochondria in transitioning adipocytes may involve both parkin-dependent and -independent pathways. Preventing the entry of beige adipocytes into white transition can be a feasible way to maintain elevated thermogenesis and energy expenditure.

SAMM50 Regulates Thermogenesis of Beige Adipocytes Differentiated from Human Adipose-Derived Stem Cells by Balancing Mitochondrial Dynamics

“…Specifically, mitophagy can induce mitochondrion degradation through PINK1-Parkin-mediated autophagy [ 20 ]. Moreover, recent studies have shown that mitophagy is involved in the conversion of beige adipocytes to white adipocytes in humans [ 19 ]. Recently, SAMM50 has been reported as a key regulator of PINK1-Parkin-mediated mitophagy and mitochondrial dynamics [ 28 ].…”

“…Mitophagy plays a key role in mitochondrial quality control, which involves the degradation of defected or redundant mitochondria through a selective pathway [ 16 , 17 ]. When thermogenic stimuli are removed, beige adipocytes activate mitophagy and return to a white adipocyte phenotype [ 18 , 19 ]. Mitophagy is initiated and regulated by PTEN-induced kinase 1 (PINK1) and Parkin in defected or redundant mitochondria [ 20 ].…”

Human Abdominal Subcutaneous-Derived Active Beige Adipocytes CarryingFTOrs1421085 Obesity-Risk Alleles Exert Lower Thermogenic Capacity

“…Propidium iodide (PI, 1.5 μg/mL, 1 h) was used for nuclei labeling. Images were obtained with an Olympus FluoView 1000 (Olympus Scientific Solutions, Tokyo, Japan) confocal microscope and FluoView10-ASW (Olympus Scientific Solutions) software version 3.0, as previously described [Szatmári-Tóth et al ., 2020; Vámos et al ., 2022]. LC3 and TOM20 immunostaining images were converted to binary form, followed by processing with FIJI.…”

“…In rodents, parkin-dependent selective mitochondrial clearance (mitophagy) drives the generation of inactive – morphologically white, but reactivation capable – masked beige adipocytes [Altshuler-Keylin et al ., 2016]. In human abdominal SC adipocytes, both parkin-dependent and parkin-independent mitophagy related genes were upregulated upon ex vivo beige to white transition [Vámos et al ., 2022]. In contrast, in differentiated human primary SC and Simpson– Golabi–Behmel syndrome (SGBS) adipocytes, cAMP-induced thermogenic activation downregulated mitophagy blocking beige to white transition [Szatmári-Tóth et al ., 2020].…”

Mitochondrial autophagy in the sleeping brain

“…Alternatively, it is possible that PINK1/Parkin-independent mitophagic pathways are activated during development to compensate for PINK1 loss. Recent advances in the field allowed discovering several cell-specific PINK1/Parkin-independent mitophagy pathways, which are activated in response to specific physiological stimuli to promote mitochondrial proteome remodelling, for example during maturation of erythrocytes ( Schweers et al, 2007 ; Kundu et al, 2008 ), neuronal differentiation ( Esteban-Martinez et al, 2017 ; Ordureau et al, 2021 ), maturation of muscle cells ( Sin et al, 2016 ), and white adipose tissue transition ( Wrighton, 2016 ; Vamos et al, 2022 ). In support of the role of compensatory mechanisms are also recent publications showing that mitochondrial quality control pathways are intertwined, so that activation of one specific pathway can compensate for loss of another ( Koentjoro et al, 2017 ; Towers et al, 2021 ).…”