Abdominal Obesity May Be Due to Tissue Response to High Cortisol
The levels of an enzyme that activates glucocorticoids, including cortisol, from their inactive forms, are increased in abdominal fat tissue — abdominal obesity is a hallmark of Cushing’s syndrome — in two mouse models of glucocorticoid excess.
Importantly, the enzyme, called 11 beta-hydroxysteroid dehydrogenase type 1 (HSD-1), also was found to be significantly reduced in the brain and liver of these mice.
These findings suggest that HSD-1 reduction in glucocorticoid-target tissues may be a compensatory mechanism to cortisol excess in Cushing’s. However, an opposite response takes place in abdominal fat tissue, likely exacerbating cortisol’s weight gain effects.
As such, this tissue-specific regulation of HSD-1 levels may be responsible for the development of abdominal, or central, obesity in Cushing’s, supporting HSD-1 suppression as a potential approach to reduce this feature.
Such an experimental therapy, Sparrow Pharmaceuticals’ SPI-62, is now being tested in people with Cushing’s disease in an ongoing Phase 2 trial (NCT05307328).
The study, “Tissue-specific regulation of 11β hydroxysteroid dehydrogenase type-1 mRNA expressions in Cushing’s syndrome mouse model,” was published in the journal Steroids.
Cushing’s syndrome is characterized by abnormally high levels of glucocorticoids, such as the stress hormone cortisol.
Most cases are caused by tumors in the brain’s pituitary gland, which trigger excessive release of an hormone called ACTH. That hormone signals the adrenal glands sitting atop the kidneys to overproduce cortisol. This specific form of the condition is known as Cushing’s disease.
Since glucocorticoids are involved in metabolism regulation, high levels of these hormones often result in symptoms like central or abdominal obesity, muscle shrinkage, fatty liver, and insulin resistance.
HSD-1, the enzyme responsible for converting inactive forms of glucocorticoids into their active forms, is mainly produced in “glucocorticoid-target tissues, such as the brain (especially in the hippocampus), liver, and adipose [fat] tissue,” the researchers wrote. Of note, the hippocampus is a brain region that plays a major role in learning and memory.
While increasing research suggests HSD-1’s involvement in central obesity, the effects of glucocorticoids on HSD-1’s production in different tissues and organs remains largely unclear.
To address this, a team of researchers in Japan now analyzed the levels of HSD-1 messenger RNA (mRNA) in the hippocampus, liver, and abdominal fat tissue in two mouse models of glucocorticoid excess. Of note, mRNA is the molecule derived from DNA that serves as a template for protein production.
In the first model, two distinct doses of corticosterone — the hormone that works as cortisol in rodents — were continuously administered to healthy mice for two weeks.
The second mouse model, commonly used in Cushing’s syndrome and called CRH-Tg, produces excess levels of corticotropin-releasing hormone. That hormone promotes ACTH production and thereby increases corticosterone levels.
Results showed that, compared with a placebo, high-dose corticosteroid treatment significantly reduced HSD-1 mRNA levels in the hippocampus and liver, while significantly increasing those in abdominal fat tissue.
Similar findings were obtained when CRH-Tg mice were compared with their healthy counterparts.
In addition, these changes in HSD-1 mRNA levels were reversed after surgical removal of the adrenal glands in these mice. That result further supports a link between circulating glucocorticoids and HSD-1 levels.
These findings highlight the “differential effects of the circulating glucocorticoid excess on [HSD-1 mRNA]: inhibition [suppression] in the hippocampus and liver, and induction in abdominal adipose tissue,” the researchers wrote.
This drop in HSD-1 levels in the hippocampus and liver “might be a compensatory mechanism to escape from overexposure to circulating glucocorticoids” and avoid damage caused by these hormones, the researchers wrote.
Notably, while both mouse models showed lower HSD-1 mRNA levels in the liver, the organ still showed high fat content, suggesting that these compensatory mechanisms “could not overcome glucocorticoid-induced fatty liver,” the team wrote.
“This tissue-specific regulation could be important for the functional compensation of several glucocorticoid-target organs, such as the brain and liver, and it may also be responsible for the development of abdominal obesity in Cushing’s syndrome,” the researchers wrote.
Future studies are needed to confirm these findings and assess the therapeutic potential of suppressing HSD-1 production to lessen abdominal obesity in Cushing’s.
Notably, a previous Phase 1/2a clinical trial showed that an experimental HSD-1 suppressor, called S-707106, reduced body fat and improved blood sugar metabolism in people with Cushing’s syndrome.
In addition, Sparrow’s experimental HSD-1 suppressor SPI-62 was found to be generally well-tolerated in healthy volunteers, while effectively blocking the enzyme’s activity in the brain and fat tissue in a Phase 1 trial. A Phase 2 trial testing the investigational therapy in people with Cushing’s disease and other forms of ACTH-dependent Cushing’s is currently underway.
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