Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance

Abstract

White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB–dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.

SQSTM1/p62 Promotes Cell Growth and Triggers Autophagy in Papillary Thyroid Cancer by Regulating the AKT/AMPK/mTOR Signaling Pathway

“…Mutations in the p62 gene are strongly associated with Paget's disease of the bone (19), murine myeloid leukemia progression (20), neurodegenerative disease (21), obesity (22), vascular senescence (23), aging pathologies and cancer (24,25). p62 consists of 440 amino acids covering more than 10 domains and binding sites; hence, it is a key center of regulating multiple activities of cells, such as insulin signaling, energy balance, adipogenesis, brown adipose tissue (BAT) thermogenesis, inflammation, oxidative stress, apoptosis, etc (26)(27)(28)(29)(30).…”

The Nucleus/Mitochondria-Shuttling LncRNAs Function as New Epigenetic Regulators of Mitophagy in Cancer

“…In addition, mitophagy regulates the elimination of sperm mitochondria, thereby avoiding the inheritance of paternal mitochondrial DNA (mtDNA; Rojansky et al, 2016 ; Song et al, 2016 ). Since mitophagy plays a crucial role in maintaining mitochondrial homeostasis ( Bin-Umer et al, 2014 ), it is not surprising that defective, inadequate, or excessive mitophagy can result in pathological conditions ( Palikaras et al, 2017 ), such as neurodegenerative disease ( Um and Yun, 2017 ; Tran and Reddy, 2020 ; Wang et al, 2021 ), cardiovascular disease ( Billia et al, 2011 ; Zhang W. et al, 2016 ; Zhang et al, 2017 ; Chang et al, 2020 ), metabolic disorders ( He et al, 2021 ; Pang et al, 2021 ; Zia et al, 2021 ), inflammation ( Sliter et al, 2018 ; Lee et al, 2020 ), liver disease ( Ke, 2020 ; Kouroumalis et al, 2021 ), aging ( Richard et al, 2013 ; Cornelissen et al, 2018 ), and cancer.…”

The Role of Mitochondrial Mutations and Chronic Inflammation in Diabetes

“…Numerous studies in humans and animals have shown that adipose tissue acts as a main producer of pro-inflammatory cytokines, including TNFα, MCP-1, and IL-6. Therefore, obesity and inflammation appear to be interdependent in T2D development [32,33]. It was demonstrated that the abovementioned pro-inflammatory cytokines are tightly interconnected with the development of insulin resistance [34].…”