Involvement of lysosomal dysfunction in autophagosome accumulation and early pathologies in adipose tissue of obese mice

Abstract

Whether obesity accelerates or suppresses autophagy in adipose tissue is still debatable. To clarify dysregulation of autophagy and its role in pathologies of obese adipose tissue, we focused on lysosomal function, protease maturation and activity, both in vivo and in vitro. First, we showed that autophagosome formation was accelerated, but autophagic clearance was impaired in obese adipose tissue. We also found protein and activity levels of CTSL (cathepsin L) were suppressed in obese adipose tissue, while the activity of CTSB (cathepsin B) was significantly enhanced. Moreover, cellular senescence and inflammasomes were activated in obese adipose tissue. In 3T3L1 adipocytes, downregulation of CTSL deteriorated autophagic clearance, upregulated expression of CTSB, promoted cellular senescence and activated inflammasomes. Upregulation of CTSB promoted additional activation of inflammasomes. Therefore, we suggest lysosomal dysfunction observed in obese adipose tissue leads to lower autophagic clearance, resulting in autophagosome accumulation. Simultaneously, lysosomal abnormalities, including deteriorated CTSL function and compensatory activation of CTSB, caused cellular senescence and inflammasome activation. Our findings strongly suggest lysosomal dysfunction is involved in early pathologies of obese adipose tissue.

Protein kinase Cα drives fibroblast activation and kidney fibrosis by stimulating autophagic flux

“…In agreement with the positive effect of PKC␣ on lysosome, our findings in cultured cells demonstrated that blocking PKC␣ activity decreased the abundance of LAMP-2, a principal lysosomal membrane protein. Lysosomal dysfunction leads to lower autophagic clearance, resulting in autophagosome accumulation (41). In this study, the impaired autophagosome-lysosome fusion after PKC␣ inhibition may due to the lysosomal dysfunction.…”

Resistin inhibits neuronal autophagy through Toll-like receptor 4

“…Recent studies associate compromised autophagy with the onset of obesity, insulin resistance and type 2 diabetes (Mizunoe et al 2017, Moller et al 2017. These metabolic disorders are characterized by the alteration of energy homeostasis control and low-grade inflammation status.…”

Autophagic dysfunction in patients with Papillon-Lefèvre syndrome is restored by recombinant cathepsin C treatment

“…25 In addition, a reduction in levels some cysteine cathepsin family members, such as CatL, has been related to a compensatory transcriptional upregulation of CatB expression and autophagy dysfunction. 26 Furthermore, in patients with a lysosomal disease, such as Niemann-Pick disease, the increased expression of mature protein forms for both CatB and CatD is associated with autophagosome accumulation. 27 Our findings showed reduced enzymatic activity of CatC associated with a compensatory upregulation of mature CatB and lysosomal permeabilization.…”