Hormonal
Endoplasmic reticulum (ER) stress in adipose tissue, triggered by nutrient excess and obesity, activates inflammatory pathways (JNK, NFkB) that directly cause insulin resistance.
In obesity, fat cells become stressed, triggering an internal alarm (ER stress) that releases inflammatory signals blocking insulin. This explains why weight loss alone might not fully restore metabolic health if cellular stress persists. Interventions that reduce ER stress (like chemical chaperones in research) show promise in restoring insulin sensitivity.
Remarkably, the consequences of UPR activation have been causally linked to the development of insulin resistance through a multitude of possible mechanisms, including c-jun N-terminal kinase activation, inflammation, and oxidative stress.
Why this rating
The paper is a comprehensive review citing multiple genetic mouse models (JNK1-deficient, XBP-1 heterozygous) and human observational data linking ER stress markers to insulin resistance.
Source
Thematic review series: Adipocyte Biology. Adipocyte stress: the endoplasmic reticulum and metabolic disease
Margaret F. Gregor et al. · Journal of Lipid Research · 2007
DOI 10.1194/jlr.r700007-jlr200
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