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Stomatin modulates adipogenesis through ERK pathway and regulates fatty acid uptake and lipid droplet growth

ABSTRACT: Controlling fatty acid uptake, lipid production and storage, and metabolism of lipid droplets (LDs), is closely related to lipid homeostasis, adipocyte hypertrophy and obesity. We report here that stomatin, a major constituent of lipid rafts, participates in adipogenesis and adipocyte maturation by modulating related signaling pathways. In adipocyte-like cells, increased stomatin promotes LD growth or enlargements by facilitating LD-LD fusion, as well as fatty acid uptake from extracellular environment by recruiting effector molecules, such as FAT/CD36 translocase, to lipid rafts to promote internalization of fatty acids. Stomatin transgenic mice fed with high-fat diets exhibit obesity, insulin resistance and hepatic impairments; however, such phenotypes are not seen if feeding the transgenic animals with regular diets. Inhibitions of stomatin by gene knockdown or OB-1 pharmacological treatments inhibit adipogenic differentiation and LD growth through downregulation of PPARγ pathway. Effects of stomatin on PPARγ involve ERK signaling; however, an alternate pathway may also exist.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Cell Culture

SUBMITTER: Chen-Chung Liao

LAB HEAD: Chen-Chung Liao

PROVIDER: PXD031866 | Pride | 2022-07-05

REPOSITORIES: Pride

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Project description:Growing evidence suggests that chemicals in disparate structural classes activate specific subsets of PPARγ’s transcriptional programs to generate adipocytes with distinct phenotypes. Our objectives were to 1) establish a novel classification method to predict PPARγ-interacting and modifying chemicals and 2) create taxonomy labels to group chemicals based on their effects on PPARγ’s transcriptome and downstream metabolic functions. We tested the hypothesis that an environmental ligand highly ranked by the taxonomy, but that segregated from the therapeutic ligands, would induce white but not brite adipogensis. 3T3-L1 cells were differentiated in the presence of 76 chemicals (negative controls, synthetic nuclear receptor ligands known to influence adipocyte biology, suspected environmental PPARγ ligands). Differentiation was assessed by measuring lipid accumulation. mRNA expression was determined by highly multiplexed RNA-Seq and validated by RT-qPCR. A novel classification model was developed using an amended random forest procedure. A subset of environmental contaminants identified as strong PPARγ agonists were characterized further for lipid handling, mitochondrial biogenesis and cellular respiration in 3T3-L1 cells and primary human preadipocytes. The 76 chemicals generated a spectrum of adipogenic differentiation. We used lipid accumulation and RNA sequencing data to develop a classification system that 1) identified PPARγ agonists and 2) sorted agonists into likely white or brite adipocyte inducers. Expression of Cidec, was the most efficacious indicator for strong PPARγ activation. Two known environmental PPARγ ligands, tetrabromobisphenol A, and triphenyl phosphate, which sorted distinctly from therapeutic ligands, induced white but not brite adipocyte genes and induced fatty acid uptake but not mitochondrial biogenesis in 3T3-L1 cells. The highly ranked agonists, tonalid and quinoxyfen, also induced white adipogenesis in 3T3-L1 cells and primary human preadipocytes. A novel classification procedure accurately identified environmental chemicals as PPARγ-modifying chemicals distinct from known PPARγ-modifying therapeutics.

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Stomatin modulates adipogenesis through ERK pathway and regulates fatty acid uptake and lipid droplet growth

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