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Chronic hyperinsulinemia leads to premature senescence of human adipocytes and pro-inflammatory state

Chronically elevated blood insulin levels, or hyperinsulinemia, leads to premature senescence of human mature adipocytes and production of pro-inflammatory adipokines, according to a new study published in Nature Medicine today. The study was conducted by an international team of researchers, with researchers from the University of Eastern Finland as collaborators.

Adipocytes are much more than just a storage for excess calories – they are important secretors of a variety of hormones and cytokines (adipokines), which have a wide impact on the functions of the whole body. In obesity, human adipose tissue expands by increasing the size of existing mature adipocytes and by generating new adipocytes from progenitor cells, as mature adipocytes have been considered unable to re-enter cell cycle and proliferate. Hyperinsulinemia and increased percentage of large adipocytes have long been associated with a metabolically unhealthy, pro-inflammatory adipokine secretory profile even in lean persons, but the underlying mechanisms have remained poorly understood.

The  study published in Nature Medicine today shows that upon chronic hyperinsulinemia, human mature adipocytes re-enter cell cycle but fail to divide, resulting in premature senescence and a pro-inflammatory phenotype. These observations were made in cultured human mature adipocytes exposed to a high insulin level, and in adipose tissue biopsies of human donors with hyperinsulinemia. These metabolically unhealthy senescent cells are characterized by increased cell and nuclear size caused by endoreduplication, i.e., doubled DNA content without cell division.

In contrast to age-induced cellular senescence, premature senescence is an irreversible block of cell cycle progression at G2/M phase induced by stressful stimuli such as strong mitogens and DNA damage, and it is being increasingly recognised as a pathological mechanism behind many chronic diseases. Senescent cells are highly metabolically active, releasing increased levels of pro-inflammatory cytokines and chemokines as compared to normal aged cells.

Diabetes medicine metformin prevented premature adipocyte senescence

The study also shows that the treatment of human adipocytes with metformin, the most prescribed medication for type 2 diabetes, not only reduced cell cycle progression, but also significantly decreased the percentage of senescent cells independent of the biopsy donor’s metabolic status.

“These results suggest that inhibiting adipocyte senescence upstream of cell-cycle entry or removing senescent cells using senolytic drugs can exert anti-inflammatory effects on adipose tissue function and thus alleviate metabolic dysfunction,” Adjunct Professor Mervi T. Hyvönen from the School of Pharmacy at the University of Eastern Finland says.

For further information, please contact:

Adjunct Professor Mervi T. Hyvönen, School of Pharmacy, University of Eastern Finland,  mervi.hyvonen (at) uef.fi, +358 40 355 3826 

Professor Kirsty L. Spalding, Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden, kirsty.spalding (at) ki.se

Reference:

Li Q, Hagberg CE, Cascales HS, Lang S, Hyvönen MT, Salehzadeh F, Chen P, Alexandersson I, Terezaki E, Harms MJ, Kutschke M, Arifen N, Krämer N, Aouadi M, Knibbe C, Boucher J, Thorell A, Spalding KL. Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce. Nature Medicine, published 4 Oct 2021. DOI: 10.1038/s41591-021-01501-8. https://www.nature.com/articles/s41591-021-01501-8

Mervi Hyvönen

Grant-funded Researcher