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Loss of the armadillo-repeat protein Plakophilin 2 in obesity breaks cell cycle dynamics to breed adipocyte senescence

ABSTRACT: Plakophilin2 (PKP2) is a key component of desmosomes mostly recognized for its involvement in the fibro fatty infiltration of heart muscle under defective PKP2. While thoroughly explored in cardiomyocytes, less attention has been given to its role in fat cells. Here we report steadily increased PKP2 during adipogenesis, with expression levels reaching its apex in terminally differentiated adipocytes. Notably, the loss of this protein in adipocytes under a pro-inflammatory microenvironment demonstrates its commitment in maintaining the expression of genes required to nurture cell cycle. Then, we show that diminished expressions of this member of the armadillo repeat family in subcutaneous adipose tissue co-segregate with obesity, being normalized upon mild to intense weight loss. We also demonstrate that impaired PKP2 in human adipocytes breaks cell cycle dynamics to breed premature senescence, a key rheostat for stress induced adipose tissue dysfunction. Conversely, restoring PKP2 in inflamed adipocytes rewires E2F signalling towards re-activation of cell cycle and decreased senescence. Our findings bound the expression of PKP2 in fat cells to the physiopathology of obesity, and uncover a previously unknown defect in cell cycle and activated adipocyte senescence due to impaired PKP2.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Francisco Ortega

PROVIDER: MSV000091898 | MassIVE | Wed May 10 00:46:00 BST 2023

SECONDARY ACCESSION(S): PXD042110

REPOSITORIES: MassIVE

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Project description:Background. Obesity and body fat distribution are important risk factors for the development of type 2 diabetes and metabolic syndrome. Evidence has accumulated that this risk is related to intrinsic differences in behavior of adipocytes in different fat depots. LIM Domain Only 3 (LMO3) plays a crucial role in adipogenesis modulating the key adipogenic master switch PPARγ in human, but not mouse, visceral adipose progenitors; however, despite high expression in mature adipocytes, its function in these cells is currently unknown. Aims/Hypothesis. The aim of this study was to determine the potential involvement of LMO3-dependent pathways in the modulation of key functions of mature adipocytes during obesity. Methods. Based on a recently engineered hybrid rAAV serotype Rec2 shown to efficiently transduce both brown adipose tissue (BAT) and white adipose tissue (WAT), we delivered YFP or Lmo3 to epididymal WAT (eWAT) of C57Bl6/J mice on a high fat diet (HFD). The effects of eWAT transduction on metabolic parameters were evaluated 10 weeks later. To further define the role of LMO3 in insulin-stimulated glucose uptake, insulin signaling, adipocyte bioenergetics as well as endocrine function, experiments were conducted in 3T3-L1 adipocytes and newly differentiated human primary mature adipocytes, engineered for transient gain- or loss of LMO3 expression, respectively.Results. AAV transduction of eWAT results in strong and stable Lmo3 expression specifically in the adipocyte fraction over a course of 10 weeks with HFD feeding. Lmo3 expression in eWAT significantly improved glucose clearance and insulin sensitivity in diet-induced obesity, paralleled by increased serum adiponectin. In vitro, Lmo3 expression in 3T3-L1 adipocytes increased insulin-stimulated GLUT4 translocation and glucose uptake as well as mitochondrial oxidative capacity in addition to fatty acid oxidation. On a molecular level, LMO3 augmented PPARg activity, oxidative mitochondrial gene expression, which depended on and the expression of the PPARg co-activator Ncoa1, which was required for LMO3 effects on mitochondria and glucose uptake. In human mature adipocytes, LMO3 overexpression promoted, while silencing of LMO3 suppressed mitochondrial oxidative capacity. Conclusions. LMO3 expression in visceral adipose tissue regulates multiple genes that preserve adipose tissue functionality during obesity, such as glucose tolerance, insulin sensitivity and adiponectin secretion. Together with increased PPARγ activity, these gene expression changes promote insulin-induced GLUT4 translocation, glucose uptake in addition to increased mitochondrial oxidative capacity, limiting HFD-induced adipose dysfunction. These data add LMO3 as a novel regulator improving visceral adipose tissue function during obesity.

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Loss of the armadillo-repeat protein Plakophilin 2 in obesity breaks cell cycle dynamics to breed adipocyte senescence

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