Abstract
SummaryThe hypothalamic-pituitary-adrenal (HPA) axis forms a complex neuroendocrine system that regulates the body’s response to stress such as starvation. In contrast with the glucocorticoid receptor (GR), Zinc finger and BTB domain containing 32 (ZBTB32) is a transcription factor with poorly described functional relevance in physiology. This study shows that ZBTB32 is essential for the production of glucocorticoids (GCs) in response to starvation, since ZBTB32−/− mice fail to increase their GC production in the absence of nutrients. In terms of mechanism, GR-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32−/− mice, implicating defective cholesterol import as the cause of the poor GC synthesis. These lower GC levels are further associated with aberrations in the metabolic adaptation to starvation, which could explain the progressive weight gain of ZBTB32−/− mice. In conclusion, ZBTB32 performs a crosstalk with the GR in the metabolic adaptation to starvation via regulation of adrenal GC production.
Highlights
Since the prevalence of obesity has tripled after 1975, obesity has been associated with an increased risk of disease and has been identified as an underlying cause of death in 20% of deaths in the USA (de Cosio et al, 2021)
This study shows that Zinc finger and BTB domain containing 32 (ZBTB32) is essential for the production of glucocorticoids (GCs) in response to starvation, since ZBTB32À/À mice fail to increase their GC production in the absence of nutrients
glucocorticoid receptor (GR)-mediated upregulation of adrenal Scarb1 gene expression was absent in ZBTB32À/À mice, implicating defective cholesterol import as the cause of the poor GC synthesis
Summary
Since the prevalence of obesity has tripled after 1975, obesity has been associated with an increased risk of disease and has been identified as an underlying cause of death in 20% of deaths in the USA (de Cosio et al, 2021). Obesity is the result of an imbalance between the rate of fat synthesis and fat catabolism in white adipose tissue (WAT) and lipid-metabolizing organs (Schweiger et al, 2017). This theory is supported by stable isotope studies demonstrating that TG synthesis is increased in the fat mass of obese individuals, while TG breakdown is decreased (Arner et al, 2011). Recent evidence suggests that a similar shift in oxidative metabolism occurs in the brain during sleep, when oxidation of fatty acids and ketone bodies (KBs) partly replace glucose as a cerebral energy source (Aalling et al, 2018)
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