Abstract
Low-grade chronic inflammation and reduced differentiation capacity are hallmarks of hypertrophic adipose tissue (AT) and key contributors of insulin resistance. We identified PPARGΔ5 as a dominant-negative splicing isoform overexpressed in the AT of obese/diabetic patients able to impair adipocyte differentiation and PPARγ activity in hypertrophic adipocytes. Herein, we investigate the impact of macrophage-secreted pro-inflammatory factors on PPARG splicing, focusing on PPARGΔ5. We report that the epididymal AT of LPS-treated mice displays increased PpargΔ5/cPparg ratio and reduced expression of Pparg-regulated genes. Interestingly, pro-inflammatory factors secreted from murine and human pro-inflammatory macrophages enhance the PPARGΔ5/cPPARG ratio in exposed adipogenic precursors. TNFα is identified herein as factor able to alter PPARG splicing—increasing PPARGΔ5/cPPARG ratio—through PI3K/Akt signaling and SRp40 splicing factor. In line with in vitro data, TNFA expression is higher in the SAT of obese (vs. lean) patients and positively correlates with PPARGΔ5 levels. In conclusion, our results indicate that inflammatory factors secreted by metabolically-activated macrophages are potent stimuli that modulate the expression and splicing of PPARG. The resulting imbalance between canonical and dominant negative isoforms may crucially contribute to impair PPARγ activity in hypertrophic AT, exacerbating the defective adipogenic capacity of precursor cells.
Highlights
Obesity is a chronic, relapsing progressive disease considered a driving force for insulin resistance and type-2 diabetes (T2D) [1,2]
PPARG splicing, we measured the relative abundance of canonical and dominant negative (Pparg∆5) Pparg transcripts in the epididymal adipose tissue (AT) of a well-established mouse model of systemic inflammation [33]
In line with the downregulation of canonical Pparg transcripts (cPparg) levels and increased Pparg∆5/cPparg ratio, the expression of Adipoq, Slc2a4 and Cd36—validated Pparγ target genes—is significantly reduced (Figure 1B), as we observed in human lipid-engulfed hypertrophic adipocytes [30]
Summary
Obesity is a chronic, relapsing progressive disease considered a driving force for insulin resistance and type-2 diabetes (T2D) [1,2]. The energy surplus can induce the enlargement of adipocyte size (hypertrophy), in turn leading to hypoxia, mechanical stress of the extracellular matrix, cell death and the secretion of pro-inflammatory cytokines [6,7,8,9]. These events trigger a chronic inflammatory response, stimulating the infiltration of macrophages (MΦ), T and dendritic cells [3,4,5,9,10]. MΦ-secreted factors impair the insulin-responsiveness of AT-residing adipocytes [16,17]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
