Developmental Programming: Metabolic Tissue-Specific Changes in Endoplasmic Reticulum Stress, Mitochondrial Oxidative and Telomere Length Status Induced by Prenatal Testosterone Excess in the Female Sheep
Molecular and cellular endocrinology(2021)
摘要
Prenatal testosterone (T) excess-induced metabolic dysfunctions involve tissue specific changes in insulin sensitivity with insulin resistant, oxidative and lipotoxic state in liver/muscle and insulin sensitive but inflammatory and oxidative state in visceral adipose tissues (VAT). We hypothesized that mitochondrial dysfunction, endoplasmic reticulum (ER) stress and premature cellular senescence are contributors to the tissue-specific changes in insulin sensitivity. Markers of mitochondrial number, function, and oxidative phosphorylation (OxPhos), ER stress and cellular senescence (telomere length) were assessed in liver, muscle and 4 adipose (VAT, subcutaneous [SAT], epicardiac [ECAT] and perirenal [PRAT]) depots collected from control and prenatal T-treated female sheep at 21 months of age. Prenatal T treatment led to: (a) reduction in mitochondrial number and OxPhos complexes and increase in ER stress markers in muscle; (b) increase in fibrosis with trend towards increase in short telomere fragments in liver (c) depot-specific mitochondrial changes with OxPhos complexes namely increase in SAT and reduction in PRAT and increase in mitochondrial number in ECAT; (d) depot-specific ER stress marker changes with increase in VAT, reduction in SAT, contrasting changes in ECAT and no changes in PRAT; and (d) reduced shorter telomere fragments in SAT, ECAT and PRAT. These changes indicate insulin resistance may be driven by mitochondrial and ER dysfunction in muscle, fibrosis and premature senescence in liver, and depot-specific changes in mitochondrial function and ER stress without involving cellular senescence in adipose tissue. These findings provide mechanistic insights into pathophysiology of metabolic dysfunction among female offspring from hyperandrogenic pregnancies.
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关键词
Mitochondria,Telomere,ER stress,Metabolic tissues,Oxidative stress,Insulin sensitivity
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