Chronic stress increases DPP-4 enzyme activity, which degrades GLP-1 and disrupts the adiponectin-cathepsin K axis needed for healthy fat cell development — effects reversed by DPP-4 knockout or GLP-1 receptor activation.
Stress → DPP-4 → GLP-1 lossChronic stress increases DPP-4 enzyme activity, degrading GLP-1 peptide and disrupting healthy fat tissue development
What the researchers found
Chronic stress increased DPP-4, decreased GLP-1 levels, and disrupted adipocyte differentiation through the GLP-1/adiponectin-cathepsin K axis. DPP-4 deletion, exenatide treatment, and CTSK deletion all reversed stress-related fat tissue dysfunction.
Why it matters
Chronic stress is a growing public health crisis linked to obesity and metabolic disease. This study reveals a specific molecular pathway — DPP-4/GLP-1/adiponectin — connecting psychological stress to fat tissue dysfunction, suggesting that GLP-1 drugs or DPP-4 inhibitors could protect metabolic health during periods of chronic stress.
The numbers in context
Used three mouse genotypes (DPP4+/+, DPP4-/-, CTSK-/-) to dissect the pathway under stress and non-stress conditions.
How the study worked
In vivo study using DPP4+/+, DPP4-/-, and CTSK-/- mice under 2 weeks of chronic psychosocial stress, with exenatide (GLP-1 agonist) intervention. In vitro studies using 3T3-L1 preadipocytes with CTSK silencing/overexpression. Measured plasma DPP4/GLP-1/CTSK/adiponectin, adipose tissue morphology, gene/protein expression, and macrophage infiltration.
Who was studied
Wild-type, DPP4-knockout, and CTSK-knockout mice under chronic psychosocial stress
What this study cannot tell us
Mouse chronic stress model may not fully replicate human psychological stress. Two-week duration is relatively short for chronic stress effects. The complex multi-knockout design makes pathway isolation challenging. Fat tissue biology differs between mice and humans.
How to read the evidence
Moderate evidence: comprehensive mouse study using multiple knockout models and both in vivo/in vitro approaches, published in FASEB Journal. No human data.
When this study was published
Published in 2024 in the FASEB Journal. Novel finding connecting psychological stress to GLP-1/DPP-4 axis disruption in fat tissue.
The bigger picture
This study adds a metabolic dimension to the stress-disease connection. DPP-4 inhibitors (like sitagliptin) and GLP-1 drugs (like semaglutide) are already prescribed to millions. If chronic stress amplifies DPP-4 activity and GLP-1 degradation, these existing drugs may provide metabolic protection beyond their primary diabetes indications for stressed populations.
Questions still open
- Do people with chronic stress show elevated DPP-4 levels and impaired GLP-1 signaling?
- Could DPP-4 inhibitors or GLP-1 drugs prevent stress-related metabolic dysfunction in clinical studies?
- Is the stress-DPP-4-GLP-1 pathway relevant to stress-induced obesity in humans?
Common questions
Can chronic stress affect my metabolism?
Could diabetes drugs protect against stress-related metabolic damage?
Read the original research
Dipeptidyl peptidase-4 disturbs adipocyte differentiation via the negative regulation of the glucagon-like peptide-1/adiponectin-cathepsin K axis in mice under chronic stress conditions.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38(10), e23684
Citation
Zhang, Meiping; Yue, Xueling; Xu, Shengnan; Piao, Jinshun; Zhao, Longguo; Shu, Shangzhi; Kuzuya, Masafumi; Li, Ping; Hong, Lan; Kim, Weon; Liu, Bin; Cheng, Xian Wu. (2024). Dipeptidyl peptidase-4 disturbs adipocyte differentiation via the negative regulation of the glucagon-like peptide-1/adiponectin-cathepsin K axis in mice under chronic stress conditions.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 38(10), e23684. https://doi.org/10.1096/fj.202400158R