MATERNAL OBESITY INDUCED INFLAMMATORY RESPONSE IMPAIRS EMBRYONIC MUSCLE & BROWN ADIPOSE TISSUE DEVELOPMENT

Md Nazmul Hossain

Maternal obesity (MO) has become a major global health concern due to its adverse effects on muscle growth, brown adipose tissue (BAT) development, and long-term metabolic health in offspring. MO disrupts muscle and BAT development, promotes fibrotic infiltration, and impairs the metabolic health of offspring in adulthood. The embryonic and fetal stages are crucial periods for myogenesis and BAT formation; however, the underlying mechanisms through which MO disrupt these developmental processes remain poorly understood. Revealing these mechanisms is essential for protecting embryos from the detrimental effects of MO, improving muscle and BAT development, and reducing the risk of metabolic diseases in offspring. This dissertation investigated the underlying mechanisms of enhanced fibrogenesis in embryonic muscle and the disruption of primary myogenesis and BAT development during embryonic and fetal development. 1) Using single-cell transcriptomic analysis of embryos at E9.5, 11.5 and 13.5 from lean and obese mice, we found that MO induces a low-grade inflammatory condition and activates transforming growth factor-β (TGFβ) signaling. Elevated TGFβ signaling promoted the fibrogenic differentiation of mesenchymal progenitor cells, resulting in an increase in the fibroblast cell population in embryonic muscle tissue at E13.5 due to MO. AMP-activated protein kinase (AMPK) is an inhibitor of TGFβ signaling, and MO-induced suppression of AMPK contributes to enhanced TGFβ activation in embryos. Treatment of obese mothers with metformin during early pregnancy to activate AMPK inhibited TGFβ signaling and reduced fibrogenesis in embryonic muscle. 2) Myogenin (Myog) is a key regulator of myoblast fusion and myotube formation during primary myogenesis. We found that MO-induced inflammatory signaling activates RelA through the canonical nuclear factor kappa B (NF-κB) signaling. RelA suppressed Myog expression by binding to a novel distal enhancer and impaired myotube formation. 3) MO impairs fetal BAT development and their thermogenic capacity, potentially increasing susceptibility of offspring to metabolic disorders in later life. Using single-cell RNA sequencing of murine embryonic interscapular BAT (iBAT) depot from E11.5 to E18.5, we identified a transcription factor JUNB, which is expressed during the lineage commitment and differentiation of brown adipocyte (BA) progenitor cells. MO-induced pro-inflammatory cytokine TNFα upregulated activation of JUNB in BA progenitor cells and inhibited their differentiation by suppressing CCAAT/enhancer-binding protein β (C/EBPβ), a crucial transcription factor required for the initiation of adipogenic differentiation and the activation of downstream differentiation factors. In summary, our studies identified key mechanisms by which MO enhances fibrogenesis, disrupts embryonic myogenesis, and impairs BAT development. These findings also suggest that targeting inflammatory signaling pathways could be a therapeutic strategy to enhance embryonic muscle and BAT development and improve the overall health of offspring in later stages of life.

MATERNAL OBESITY INDUCED INFLAMMATORY RESPONSE IMPAIRS EMBRYONIC MUSCLE & BROWN ADIPOSE TISSUE DEVELOPMENT

Files and links (1)

Abstract

Metrics

Details