Depletion of Adipocyte Becn1 Leads to Lipodystrophy and Metabolic Dysregulation

Abstract

Becn1/Beclin-1 is a core component of the class III phosphatidylinositol 3-kinase required for autophagosome formation and vesicular trafficking. Although Becn1 has been implicated in numerous diseases such as cancer, aging, and neurodegenerative disease, the role of Becn1 in white adipose tissue and related metabolic diseases remains elusive. In this study, we show that adipocyte-specific Becn1 knockout mice develop severe lipodystrophy, leading to adipose tissue inflammation, hepatic steatosis, and insulin resistance. Ablation of Becn1 in adipocytes stimulates programmed cell death in a cell-autonomous manner, accompanied by elevated endoplasmic reticulum (ER) stress gene expression. Furthermore, we observed that Becn1 depletion sensitized mature adipocytes to ER stress, leading to accelerated cell death. Taken together, these data suggest that adipocyte Becn1 would serve as a crucial player for adipocyte survival and adipose tissue homeostasis.

Transcriptome Analysis Reveal Candidate Genes and Pathways Responses to Lactate Dehydrogenase Inhibition (Oxamate) in Hyperglycemic Human Renal Proximal Epithelial Tubular Cells

“…BECN1 is a haploinsufficient tumor suppressor gene as a core component of the class III phosphatidylinositol 3-kinase that is involved in autophagosome formation and vesicular trafficking ( 37 ). It has been suggested that BECN1 was required for mitophagy completion, and suppressed mitophagy by BECN1 deficiency could cause aberrant mitochondria quality control in adipocyte to cause lipodystrophy and metabolic dysregulation ( 38 ). The qRT-PCR experiment results of MAP1LC3A (adjusted P -value = 1.30×10 -3 and log 2 (FC) = 0.71) and MAP1LC3B (adjusted P -value = 8.47×10 -4 and log 2 (FC) = 0.35) showed higher expression levels in the 40 mM oxamate treated groups than the non-treated groups after validations ( P -value < 0.01 after student’s t -test) ( Figure 3C ), which is consistent with the transcriptome results in the up-regulated status ( Supplementary File 2 ).…”

Cdkn2aregulates beige fat maintenance through BECN1-mediated autophagy

“…Consistently, early studies using adipose-specific deletion of autophagy-related genes show that mice accumulate more mitochondria in WAT, producing a browning of WAT phenotype with reduced body weight and WAT mass (Baerga et al, 2009; Zhang et al, 2009). Among the autophagy pathway, BECN1 is a scaffolding protein that is key for the initiation of autophagosome biogenesis (He and Levine, 2010), and therefore, we can target and activate autophagy at early steps; the role of BECN1 in adipose tissue has been recently appreciated: adipocyte-specific BECN1 knockout mice develop severe lipodystrophy and metabolic dysfunctions (Jin et al, 2021; Son et al, 2020). However, it is not clear what role BECN1 plays in UCP1 + cells and whether BECN1 mediates beige activity downstream of the Cdkn2a pathway.…”

Degradative and Non-Degradative Roles of Autophagy Proteins in Metabolism and Metabolic Diseases

“…Although the impact of Atg7 deletion in mature adipocytes remains to be determined, other studies have shown that autophagy also plays an important role in the regulation of post-developmental functions and homeostasis of mature adipocytes. Different from KO of Atg7 during adipose development stages, adipocyte-specific KO of Becn1 during adulthood increases adipose tissue inflammation, ER stress and apoptosis, and decreases insulin sensitivity (Jin et al, 2021). Similarly, post-developmental adipose-specific deletion of Atg3 or Atg16L1 leads to dysfunctional mitochondria accumulation followed by increased lipid peroxides in adipose tissue, although fat mass and body weight appear to be unaffected.…”