A few months ago I did a post on a pair of studies showing that while cortisol has a negative feedback mechanism centrally, the peripheral feedback mechanism is positive. In other words, a person can have normal or even low blood levels of cortisol and very high cortisol levels in tissues, due to the ability of cortisol to increase the expression of the enzyme 11β-HSD1, which is the rate-limiting step in synthesizing cortisol and is expressed in most organs/tissues. So, the more cortisol one produces (due to stress, fasting carb-restriction, etc) the more one increases the ability to produce even more cortisol. This discrepancy between the peripheral and central feedback mechanism of cortisol is probably a major reason why most endocrinologists still do not want to admit the primary causative role cortisol plays in conditions such as diabetes II – i.e. the blood levels of cortisol in such people are often normal, or even low. However, multiple studies have demonstrated that tissue expressions of 11β-HSD1 are not only predictive of developing obesity/diabetes in the future, but are also predictive of the course of already established diabetes. As a result of this tacit admission that elevated cortisol is pathological for health (especially for metabolic conditions), a number of pharma companies are running clinical trials with 11β-HSD1 inhibitors as treatments for obesity, diabetes, dementia, sarcopenia, and even Cushing syndrome/disease. One of the criticisms I have heard from endocrinologists in regards to the positive feedback mechanism of cortisol peripherally is that most of the evidence so far is from in-vitro experiments. The in-vivo study below may be able to address that criticism by demonstrating that running daily for a few weeks doubled 11β-HSD1 expression in tissues, confirming once again that even “beneficial” stress such as “endurance” exercise is sufficient to cause peripheral state of high cortisol, which probably persists even after the stress/exercise stops since the increased expression of 11β-HSD1 is not known to downregulate on its own. In fact, a number of studies have suggested that once such peripheral hyper-cortisol state is established through increased expression of 11β-HSD1 (specifically through fasting and/or exercise), the only way to reset it back to the original (lower) levels is by using pharmacological interventions such as RU486. However, that is a prescription drug, which is currently out of stock in most suppliers due to political infighting in regards to its abortifacient use. It is also an “estrane” steroids, which means potential for causing unforseen estrogenic effects in specific organs/tissues. Thankfully, aspirin, emodin, and progesterone are also known to downregulate the expression of 11β-HSD1 and in the case of emodin and progesterone, they inhibit the actual activity of 11β-HSD1, and also increase activity of the cortisol-deactivating enzyme 11β-HSD2.
https://doi.org/10.1152/japplphysiol.00652.2016
“…In summary, we report that 6 wk of treadmill training leads to a significant increase in pulmonary corticosterone levels in ob/ob mice, which is in parallel with the favorable effects of exercise on obesity-associated pulmonary inflammation. We demonstrate for the first time that exercise training increases pulmonary 11β-HSD1 expression but has no significant effect on pulmonary 11β-HSD2 expression in both lean and ob/ob mice.”
