In the body's ongoing effort to maintain a healthy weight, an arsenal of cellular proteins called androgen receptors is critical for blocking fat accumulation. Now researchers reporting in the September issue of the Cell Press Journal Chemistry & Biology have discovered that naturally occurring steroids called glucocorticoids can thwart the receptors' activity, ultimately encouraging fat buildup.
"This has implications in this era of an obesity epidemic," says senior author Dr. Michael Mancini, from Baylor College of Medicine. "If you can reduce glucocorticoids, you might be able to upregulate, or increase, androgen receptor activity and regulate fat storage."
The discovery came after Dr. Mancini and his team searched for genes or signals expressed specifically by human fat cells with the hope of gaining a better understanding of fat deposition and the development of obesity. They used a novel approach that combined gene expression studies with automated microscopy and specialized image analyses.
The approach showed that the androgen receptor is both expressed and functional during the early stages of fat cell differentiation. "Activation of the androgen receptor can inhibit the early stages of human fat maturation," says first author Dr. Sean Hartig, also from Baylor College of Medicine. The finding makes sense because androgens such as testosterone, which bind to androgen receptors, are known to favorably direct muscle differentiation, regulate muscle mass, and increase lean body mass as humans age.
The researchers also found that glucocorticoids decrease androgen receptor activity and alter the effects of androgens on fat storage. The result is deposition of fat throughout the body, particularly in the abdominal region. "Using a custom-developed image analysis software platform usually found only in large pharmaceutical screening centers, we applied specific algorithms to sensitively detect the glucocorticoid inhibition of androgen receptor activity," says Dr. Mancini.
The research suggests that treatment strategies that modulate the activity of glucocorticoids and the androgen receptor--perhaps in combination--may help combat obesity.
Hartig et al.: "Feed-forward Inhibition of Androgen Receptor Activity by Glucocorticoid Action in Human Adipocytes."