Depletion of ASK1 blunts stress-induced senescence in adipocytes
Stephan Wueest1,2, Fabrizio C Lucchini1,2,3, Yulia Haim4,5
1Division of Pediatric Endocrinology and Diabetology, University Children's Hospital , Zurich, Switzerland.
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.
Insights
Apoptosis signal-regulating kinase 1 (ASK1) plays a key role in inducing cellular senescence in white adipocytes. Inhibiting ASK1 may offer a therapeutic strategy for obesity and related metabolic disorders.
Area of Science:
- Metabolic research
- Cellular senescence
- Adipose tissue biology
Background:
- Increasing energy expenditure by inducing browning in white adipose tissue is a promising strategy for obesity treatment.
- Previous studies showed ASK1 inhibition protects against diet- or LPS-induced UCP1 downregulation in adipocytes.
- ASK1 overexpression in adipocytes attenuates cold-induced UCP1 expression.
Purpose of the Study:
- To investigate the role of ASK1 in TNFα-mediated and high-fat diet (HFD)-induced p38 MAPK activation in white adipocytes.
- To determine the effect of ASK1 on stress-induced senescence in adipocytes.
Main Methods:
- Utilized adipocyte-specific ASK1 knockout mice fed a high-fat diet (HFD).
- Assessed senescence markers in adipocytes from HFD-fed mice.
- Depleted ASK1 in adipocytes and evaluated lipopolysaccharide (LPS)-induced senescence markers.
Main Results:
- Confirmed that TNFα-mediated and HFD-induced p38 MAPK activation in white adipocytes is dependent on ASK1.
- Observed reduced expression of senescence markers in HFD-fed adipocyte-specific ASK1 knockout mice.
- Found that LPS-induced upregulation of senescence markers was blunted in ASK1-depleted adipocytes.
Conclusions:
- Identified a novel role for ASK1 in the induction of stress-induced senescence in white adipocytes.
- Suggests ASK1 inhibition as a potential therapeutic target for obesity and associated metabolic complications.
