Dataset Information

Transcriptome analysis of ciliary-dependent MCH signaling in differentiating 3T3-L1 pre-adipocytes.

ABSTRACT: An understanding of adipocyte responsiveness to G-protein-coupled receptor-(GPCR) derived signals must take into consideration the role of membrane microenvironments; that individual sub-populations of proteins may vary significantly across different regions of the cell, and that cell differentiation alters those microenvironments. 3T3-L1 pre-adipocytes undergo a dramatic phenotypic transformation during differentiation into adipocytes, requiring the development of a transient primary cilium. We demonstrate that melanin-concentrating hormone (MCH) receptor 1, a GPCR that stimulates appetite, translocates to the transient primary cilium during early 3T3-L1 cell adipogenesis. Furthermore, we used RNA-Seq to investigate whether MCH signaling is influenced by its receptor localization and whether MCH can influence the transcriptome of early adipocyte development. We found that MCH signaling is sensitive to receptor localization to cilia, and this alters the adipogenic transcriptional program. Also, novel MCH signaling pathways in 3T3-L1 cells are identified, including those for circadian rhythm, the inflammatory response, and ciliary biogenesis. The presence of active MCH-signaling pathways in pre-adipocytes and the discovery that these pathways intersect with the early adipogenic program, among other newly-identified signaling pathways, suggests that the use of MCH receptor 1 antagonists for clinical interventions may have unintended consequences on adipose tissue development.

SUBMITTER: Cook LB

PROVIDER: S-EPMC7921120 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Transcriptome analysis of ciliary-dependent MCH signaling in differentiating 3T3-L1 pre-adipocytes.

Cook Laurie B LB Ophardt Henry D HD Shen Rongkun R Pratt Bryan H BH Galbier Lucas A LA

Scientific reports 20210301 1

An understanding of adipocyte responsiveness to G-protein-coupled receptor-(GPCR) derived signals must take into consideration the role of membrane microenvironments; that individual sub-populations of proteins may vary significantly across different regions of the cell, and that cell differentiation alters those microenvironments. 3T3-L1 pre-adipocytes undergo a dramatic phenotypic transformation during differentiation into adipocytes, requiring the development of a transient primary cilium. We ...[more]

PMID: 33649390

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Project description:The differentiation of precursor cells into mature adipocytes (adipogenesis) has been an area of increased focus, spurred by a rise in obesity rates. Though our understanding of adipogenesis and its regulation at the cellular level is growing, many questions remain, especially regarding the regulation of the metabolome. The 3T3-L1 cell line is the most well characterized cellular model of adipogenesis. Using a time course metabolomics approach, we show that the 3T3-L1 preadipocyte metabolome is greatly altered during the first 48 hours of differentiation, where cells go through about two rounds of cell division, a process known as mitotic clonal expansion. Short-chain peptides were among several small molecules that were increased during mitotic clonal expansion. Additional indicators of protein turnover were also increased, including bilirubin, a degradation product of heme-containing proteins, and 3-methylhistidine, a post-translationally modified amino acid that is not reutilized for protein synthesis. To study the origin of the peptides, we treated differentiating preadipocytes with 18O labeled water and found that 18O was incorporated into the short chain peptides, confirming them, at least in part, as products of hydrolysis. Inhibitors of the proteasome or matrix metalloproteinases affected the peptide levels during differentiation, but inhibitors of autophagy or peptidases did not. 18O was also incorporated into several choline metabolites including cytidine 5'-diphosphocholine (CDP-choline), glycerophosphocholine, and several phosphatidylcholine species, indicative of phosphatidylcholine synthesis/degradation and of flux through the CDP-choline cycle, a hallmark of proliferating cells. 18O-Tracer metabolomics further showed metabolic labeling of glutamate, suggestive of glutaminolysis, also characteristic of proliferating cells. Together, these results highlight the utility of 18O isotope labeling in combination with metabolomics to uncover changes in cellular metabolism that are not detectable by time-resolved metabolomics.

Dataset Information

Transcriptome analysis of ciliary-dependent MCH signaling in differentiating 3T3-L1 pre-adipocytes.

Publications

Transcriptome analysis of ciliary-dependent MCH signaling in differentiating 3T3-L1 pre-adipocytes.

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