# Insulin-stimulated glucose uptake is impaired in senescent human adipocytes

## TL;DR

This study shows that aging-related cell senescence in fat cells reduces their ability to take up glucose when insulin is present, which could contribute to poor glucose control and fat buildup.

## Contribution

The study demonstrates for the first time that senescent human adipocytes exhibit impaired insulin-stimulated glucose uptake despite intact insulin signaling.

## Key findings

- Insulin-stimulated glucose uptake is significantly reduced in senescent adipocytes.
- GLUT4 expression and adiponectin secretion are decreased in senescent adipocytes.
- Lipolytic capacity remains largely unaffected in senescent adipocytes.

## Abstract

Cell senescence, a state of cell cycle arrest induced by intrinsic or extrinsic stress, is linked to aging and aging-associated diseases. Senescence markers are elevated in adipose tissue with age and in obesity. Recently, it was shown that human mature adipocytes can undergo senescence in response to hyperinsulinemia. However, the functional consequences of adipocyte cell senescence remain poorly understood.

To study the impact of cellular senescence on human adipocyte function, we induced senescence in differentiated primary human preadipocytes (referred to as human adipocytes) using nutlin-3a, doxorubicin and etoposide. Expression of senescence markers, insulin receptor signaling, response to lipolytic stimuli and insulin mediated glucose uptake were investigated.

The senescence-inducing compounds increased expression of senescence markers p21, p53, activity of senescence-associated β-galactosidase (SA-βgal) and secretion of senescence-associated secreted factors (SASP). We showed that insulin-stimulated glucose uptake, but not basal glucose uptake, was significantly reduced in senescent adipocytes. Insulin receptor signaling was largely unaffected, while expression of insulin receptor signaling proteins and especially GLUT4 expression were reduced. Expression of some adipocyte marker genes, including ADIPOQ, LEP, PNPLA2, LIPE and PPARγ2, and secretion of adiponectin were reduced in the senescent adipocytes. In contrast, lipolytic capacity of senescent adipocytes was largely unaffected.

Our findings indicate that cellular senescence impairs insulin-stimulated glucose uptake but not lipolytic capacity; changes that may contribute to impaired glucose control and ectopic fat accumulation.