Metabolic Changes in Cushing’s Likely Mediated by Organ Interactions, Mouse Study Suggests

Excess glucocorticoid levels in Cushing’s syndrome induces whole-body metabolic changes that are likely mediated by an inter-communication between different organs, a mouse study suggests.

The study, “Correlation among body composition and metabolic regulation in a male mouse model of Cushing’s syndrome,” was published in the Endocrine Journal.

Cushing’s syndrome is a condition characterized by high levels of the hormone cortisol in the blood stream, either due to factors within the body — normally a benign tumor — or due to external factors, such as prolonged use of corticosteroid medications.

Glucocorticoids such as cortisol are involved in metabolism regulation. Thus, high levels of these hormones often result in symptoms such obesity, muscle shrinkage (atrophy), fatty liver, and insulin resistance in Cushing’s syndrome patients.

While glucocorticoids exert their effects by binding to the glucocorticoid receptor, some studies have suggested that this receptor is not always needed for glucocorticoid-mediated metabolic changes. Rather, metabolic changes in one organ may be directly influenced by the metabolic state of another organ.

In a previous study, researchers demonstrated that mice without the glucocorticoid receptor in skeletal muscle cells had smaller adipose (fat) tissues, and that this effect was mediated by the liver, suggesting an interplay between different organs in the body.

Now they’ve investigated the role of glucocorticoids in whole-body metabolism using a male mouse model of Cushing’s syndrome, created by treating mice for four weeks with corticosterone in drinking water. Control mice were treated with a vehicle (innocuous substance) in their drinking water.

The researchers looked at the effects of glucocorticoids on multiple organs including the liver, skeletal muscle, and fat tissue, and the relationships between these organs.

After four weeks on corticosterone, the mice showed changes associated with excess glucocorticoid levels, including increased body weight, reduced adrenal gland weight, and an increased tendency to experience high levels of glucose and insulin, compared to the control mice.

The researchers also detected changes in body composition and energy metabolism, including accumulation of fat in the liver, an abnormal amount of blood lipids, increase in fat tissue, muscle wasting, glucose intolerance, and insulin resistance.

The release of glucocorticoids from the adrenal glands is regulated by the body’s central stress response system, called the hypothalamic-pituitary-adrenal (HPA) axis. When too much cortisol is found in the blood, the adrenal glands are signaled to stop producing cortisol, in an attempt to balance cortisol levels. A lower adrenal gland weight is thought to reflect the HPA axis action on suppressing glucocorticoid excess.

The team went on to explore the relationship between adrenal gland weight and metabolic parameters in muscle and adipose tissue, including the weight of these organs, and blood levels of insulin, triglycerides (a type of fat), liver enzymes, and FGF21 (a liver hormone that controls fat breakdown in periods of high energy expenditure).

Adrenal gland weight significantly correlated, positively or negatively, with all of these metabolic parameters, with the exception of soleus (a lower leg muscle thought to be glucocorticoid-resistant).

Almost all pairs of metabolic parameters significantly correlated with each other. However, the weights of erector spinae (muscles that surround the spine) and gastrocnemius (back lower leg muscle) negatively correlated with the other metabolic parameters despite being glucocorticoid-sensitive tissues.

An imaging scan (known as micro-CT scan) was then used to assess the effects of excess cortisol on the body composition of different organs. The cross-sectional areas of the liver, inguinal fat tissue (located above the hind limbs), and retroperitoneal fat tissue (along the dorsal wall of the abdomen) were increased in the corticosterone-treated mice compared to controls.

Consistent with prior findings, the cross-sectional area of the erector spinae was decreased in Cushing’s animals.

The results of these analyses indicate that communication between organs such as skeletal muscle, liver, and fat may occur in Cushing’s syndrome. However, it is not yet fully clear whether this is driven by metabolic factors or other hormones.

“In conclusion, the present study may indicate that glucocorticoid excess alters metabolic phenotype and body composition most possibly via the inter-organ communication among skeletal muscle, liver, and adipose tissues,” researchers wrote.

“Together with our previous report, we may also suggest that such inter-organ communication is conditionally regulated. More comprehensive approach should be needed to unveil complex regulatory mechanism for systemic metabolism,” they said.