336 Diet-induced obesity impairs the antimicrobial defense function of dermal adipocyte progenitors

Infections are a major complication of obesity, but the mechanisms responsible for impaired defense against microbes are not well understood. Here, we found that adipocyte progenitors were lost from the dermis during diet-induced obesity (DIO) in humans and mice. The loss of adipogenic fibroblasts from mice resulted in less antimicrobial peptide production and greatly increased susceptibility to Staphylococcus aureus infection. The decrease in adipocyte progenitors in DIO mice was explained by expression of transforming growth factor–β (TGFβ) by mature adipocytes that then inhibited adipocyte progenitors and the production of cathelicidin in vitro. Administration of a TGFβ receptor inhibitor or a peroxisome proliferator–activated receptor–γ agonist reversed this inhibition in both cultured adipocyte progenitors and in mice and subsequently restored the capacity of obese mice to defend against S. aureus skin infection. Together, these results explain how obesity promotes dysfunction of the antimicrobial function of reactive dermal adipogenesis and identifies potential therapeutic targets to manage skin infection associated with obesity.

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Link between mast cells and bacteria: Antimicrobial defense, function and regulation by cytokines

Medical Hypotheses ◽

10.1016/j.mehy.2017.06.018 ◽

2017 ◽

Vol 106 ◽

pp. 10-14 ◽

Cited By ~ 7

Author(s):

Pio Conti ◽

Francesco Carinci ◽

Alessandro Caraffa ◽

Gianpaolo Ronconi ◽

Gianfranco Lessiani ◽

...

Keyword(s):

Mast Cells ◽

Antimicrobial Defense ◽

Defense Function

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The negative adipogenesis regulator DLK1 is transcriptionally regulated by TIS7 (IFRD1) and translationally by its orthologue SKMc15 (IFRD2)

10.1101/719922 ◽

2019 ◽

Author(s):

Ilja Vietor ◽

Domagoj Cikes ◽

Kati Piironen ◽

Ronald Gstir ◽

Matthias David Erlacher ◽

...

Keyword(s):

Wnt Signaling ◽

Cell Fate ◽

High Fat Diet ◽

Adipocyte Differentiation ◽

Negative Regulator ◽

Protein Levels ◽

Diet Induced Obesity ◽

Fatty Acid Transporter ◽

Adipocyte Progenitors ◽

Translational Inhibitor

AbstractDelta-like homolog 1 (DLK1), an inhibitor of adipogenesis, controls the cell fate of adipocyte progenitors. Understanding regulatory mechanisms affecting DLK1 levels is therefore of high interest. Here we identify two independent mechanisms, transcriptional and translational, by which TIS7 (IFRD1) and its orthologue SKMc15 (IFRD2) regulate DLK1 levels. Mice deficient in both TIS7 and SKMc15 (dKO) had severely reduced adipose tissue and were resistant to high fat diet-induced obesity. Wnt signaling, a negative regulator of adipocyte differentiation was significantly up regulated in dKO mice. Elevated levels of the Wnt/β-catenin target protein Dlk-1 inhibited the expression of adipogenesis regulators PPARγ and C/EBPα, and fatty acid transporter CD36. Although both, TIS7 and SKMc15, contributed to this phenotype, they utilized two different mechanisms. TIS7 acted by controlling Wnt signaling and thereby transcriptional regulation of Dlk-1. On the other hand, here we provide experimental evidence that SKMc15 acts as a general translational inhibitor affecting DLK-1 protein levels. Our study provides data describing novel mechanisms of DLK1 regulation in adipocyte differentiation involving TIS7 and SKMc15.

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