The hypothalamic-pituitary adrenal (HPA) axis plays a key role in the metabolic response to stress, so it is to be anticipated that cortisol signalling might in turn be regulated by nutritional status. This regulation might operate either centrally, controlling ACTH and hence plasma cortisol, or peripherally, controlling metabolism of cortisol in target tissues.
Plasma cortisol levels are elevated during starvation in animals and a recent meta-analysis confirms that starvation elevates plasma cortisol also in humans, although the effect may be transient. Cortisol levels also rise transiently after meals in humans. It is usually assumed that these effects of starvation and feeding are mediated by central alterations in the HPA axis. However, using stable isotope steroid tracers and test meals with different macronutrient components, we demonstrated that enhanced peripheral regeneration of cortisol contributes substantially to the rise in plasma cortisol after consumption of carbohydrate but not fat. We further demonstrated acute up-regulation of 11β-HSD1 activity in vivo by insulin but not lipid infusions.
With chronic dietary manipulation in humans, however, a low carbohydrate diet induces up-regulation of 11β-HSD1, an effect which is mimicked by metformin administration, suggesting that hyperinsulinaemia may chronically down-regulate 11β-HSD1. Indeed, in obesity without diabetes 11β-HSD1 is down-regulated in liver. However, other factors may come into play in obesity, particularly up-regulation of adipose 11β-HSD1 induced by intra-adipose inflammation. A complex regulation of 11β-HSD1 by pathways involved in nutrient signalling appears to be species- and tissue-specific, e.g. Tith changes induced by PPAR agonists and growth hormone in mice not readily recapitulated in humans.
We conclude that both the HPA axis and peripheral regeneration of cortisol are influenced by nutritional status and dietary macronutrient content. Variations in glucocorticoid signalling may therefore contribute to adverse effects not only of total calorie excess, but also specific dietary components.
Disclosure: British Heart Foundation.