Cells, Vol. 11, Pages 42: TNFα Mediates Inflammation-Induced Effects on PPARG Splicing in Adipose Tissue and Mesenchymal Precursor Cells
Low-grade chronic inflammation and reduced differentiation capacity are hallmarks of hypertrophic adipose tissue (AT) and key contributors of insulin resistance. We identified PPARG&Delta;5 as a dominant-negative splicing isoform overexpressed in the AT of obese/diabetic patients able to impair adipocyte differentiation and PPAR&gamma; activity in hypertrophic adipocytes. Herein, we investigate the impact of macrophage-secreted pro-inflammatory factors on PPARG splicing, focusing on PPARG&Delta;5. We report that the epididymal AT of LPS-treated mice displays increased Pparg&Delta;5/cPparg ratio and reduced expression of Pparg-regulated genes. Interestingly, pro-inflammatory factors secreted from murine and human pro-inflammatory macrophages enhance the PPARG&Delta;5/cPPARG ratio in exposed adipogenic precursors. TNF&alpha; is identified herein as factor able to alter PPARG splicing&mdash;increasing PPARG&Delta;5/cPPARG ratio&mdash;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 PPARG&Delta;5 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 PPAR&gamma; activity in hypertrophic AT, exacerbating the defective adipogenic capacity of precursor cells.
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