Depletion of ASK1 blunts stress-induced senescence in adipocytes

ABSTRACT

Increasing energy expenditure via induction of browning in white adipose tissue has emerged as a potential strategy to treat obesity and associated metabolic complications. We previously reported that ASK1 inhibition in adipocytes protected from high-fat diet (HFD) or lipopolysaccharide (LPS)-mediated downregulation of UCP1 both in vitro and in vivo. Conversely, adipocyte-specific ASK1 overexpression attenuated cold-induction of UCP-1 in inguinal fat. Herein, we provide evidence that both TNFα-mediated and HFD-induced activation of p38 MAPK in white adipocytes are ASK1-dependent. Moreover, expression of senescence markers was reduced in HFD-fed adipocyte-specific ASK1 knockout mice. Similarly, LPS-induced upregulation of senescence markers was blunted in ASK1-depleted adipocytes. Thus, our study identifies a previously unknown role for ASK1 in the induction of stress-induced senescence.

KEYWORDS:

• Obesity
• diabetes
• browning
• adipose tissue
• subcutaneous
• lipopolysaccharide
• p38 MAPK

Disclosure statement

The authors declare no conflict of interest.

Additional information

Funding

This work was supported by a grant from the Swiss National Science Foundation (#310030-160129 and #310030-179344 to DK), a grant from the Children’s Research Centre of the University Children’s Hospital Zurich (to SW) and a grant from the Israel Science Foundation (#ISF 2176/19 to AR).