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Anti-PDGFcc antibody treatment increases adipogenesis pathways in inguinal white adipose tissue

ABSTRACT: Purpose: The goals of this experiment were to examine the transcriptional profiles (RNA-seq) of inguinal white adipose tissue (iWAT) in mice subjected to the indicated diets and treatments for eight weeks. Methods: 6-week-old C57BL6/J mice fed a control or a high-fat diet were treated with anti-PDGFcc neutralizing antibodies or Goat IgG for 2 weeks of treatment. Antibodies were administered by i.p. every two days. Four animals were treated in each condition. The resulting iWAT from these mice were sequenced in duplicates, aligned with STAR, quantified with featureCounts, and then differential gene expression analyses were performed using limma. Results: An unbiased analysis of hallmark pathways in iWAT of anti-PDGFcc antibody-treated mice and control animals using a pre-ranked Gene Set Enrichment Analysis (GSEA) identified adipogenesis as the pathway most differentially regulated by PDGFcc blockade when accounting for diet effects. By contrast, the hallmark fatty acid metabolism pathway which includes genes involved in lipid uptake, lipid oxidation, and lipid mobilization was not significantly enriched after anti-PDGFcc treatment. Similarly, hallmark pathways glycolysis, MTORC1 signaling, or TGFb signaling were not differentially regulated by anti-PDGFcc treatment after accounting for diet effects. An additional GSEA analysis of genes involved in lipid synthesis and storage identified a subset of genes up-regulated by PDGFcc blockade regardless of diet, which included several negative regulators of lipid synthesis and storage such as Insig1, Ppara, and Idh2. Conclusions: A GSEA identified adipogenesis as the pathway most differentially regulated by PDGFcc blockade when accounting for diet effects. Key genes involved included several negative regulators of lipid synthesis and storage such as Insig1, Ppara, and Idh2.

ORGANISM(S): Mus musculus

PROVIDER: GSE169226 | GEO | 2021/03/20

REPOSITORIES: GEO

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Project description:Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic JAK-STAT activation, reduced insulin sensitivity and hyperglycaemia, and a shorter lifespan. Drosophila macrophages scavenged lipids and produced the type 1 cytokine upd3, in a scavenger-receptor (croquemort) and JNK-dependent manner. Genetic depletion of macrophages, or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-M-NM-:B signalling made no contribution to the phenotype observed. These results identify an evolutionarily conserved M-bM-^@M-^Xscavenger receptor-JNK-Type 1 cytokineM-bM-^@M-^Y cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway Long-term consumption of fatty foods is associated with obesity, macrophage activation and inflammation, metabolic imbalance, and a reduced lifespan. We took advantage of Drosophila genetics to investigate the role of macrophages and the pathway(s) that govern their response to dietary stress. Flies fed a lipid-rich diet presented with increased fat storage, systemic JAK-STAT activation, reduced insulin sensitivity and hyperglycaemia, and a shorter lifespan. Drosophila macrophages scavenged lipids and produced the type 1 cytokine upd3, in a scavenger-receptor (croquemort) and JNK-dependent manner. Genetic depletion of macrophages, or macrophage-specific silencing of upd3 decreased JAK-STAT activation and rescued insulin sensitivity and the lifespan of Drosophila, but did not decrease fat storage. NF-M-NM-:B signalling made no contribution to the phenotype observed. These results identify an evolutionarily conserved M-bM-^@M-^Xscavenger receptor-JNK-Type 1 cytokineM-bM-^@M-^Y cassette in macrophages, which controls glucose metabolism and reduces lifespan in Drosophila maintained on a lipid-rich diet via activation of the JAK-STAT pathway 5 biological samples were FACS-sorted from different batches of Drosophila melanogaster males after 30 days on 15% lipid enriched diet (n=5) and control diet (n=5)

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Anti-PDGFcc antibody treatment increases adipogenesis pathways in inguinal white adipose tissue

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