Context-dependent regulation of lipid accumulation in adipocytes by a HIF1α-PPARγ feedback network.

TitleContext-dependent regulation of lipid accumulation in adipocytes by a HIF1α-PPARγ feedback network.
Publication TypeJournal Article
Year of Publication2023
AuthorsKudo T, Zhao ML, Jeknić S, Kovary KM, LaGory EL, Covert MW, Teruel MN
JournalCell Syst
Volume14
Issue12
Pagination1074-1086.e7
Date Published2023 Dec 20
ISSN2405-4720
KeywordsAdipocytes, Adipose Tissue, Feedback, Humans, Lipids, PPAR gamma
Abstract

Hypoxia-induced upregulation of HIF1α triggers adipose tissue dysfunction and insulin resistance in obese patients. HIF1α closely interacts with PPARγ, the master regulator of adipocyte differentiation and lipid accumulation, but there are conflicting results regarding how this interaction controls the excessive lipid accumulation that drives adipocyte dysfunction. To directly address these conflicts, we established a differentiation system that recapitulated prior seemingly opposing observations made across different experimental settings. Using single-cell imaging and coarse-grained mathematical modeling, we show how HIF1α can both promote and repress lipid accumulation during adipogenesis. Our model predicted and our experiments confirmed that the opposing roles of HIF1α are isolated from each other by the positive-feedback-mediated upregulation of PPARγ that drives adipocyte differentiation. Finally, we identify three factors: strength of the differentiation cue, timing of hypoxic perturbation, and strength of HIF1α expression changes that, when considered together, provide an explanation for many of the previous conflicting reports.

DOI10.1016/j.cels.2023.10.010
Custom 1

https://www.ncbi.nlm.nih.gov/pubmed/37995680?dopt=Abstract

Alternate JournalCell Syst
PubMed ID37995680
Grant ListR01 DK131432 / DK / NIDDK NIH HHS / United States
R01 DK101743 / DK / NIDDK NIH HHS / United States
R01 DK106241 / DK / NIDDK NIH HHS / United States
P50 GM107615 / GM / NIGMS NIH HHS / United States
P30 DK116074 / DK / NIDDK NIH HHS / United States
F31 DK112570 / DK / NIDDK NIH HHS / United States

Weill Cornell Medicine Gale and Ira Drukier Institute for Children's Health 413 E. 69th Street New York, NY 10021