Effects of Androgen Excess on Lipid Distribution in Congenital Adrenal Hyperplasia

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Project Summary Androgens play an intriguing role in the regulation of body fat distribution, with fundamental differences in adipose accumulation between males (apple-shaped, android) and females (pear-shaped, gynoid). Although differences in the abdominal and gluteal-femoral adipose depots have been identified for endocrine and metabolic function, adipocyte size, and gene regulation of preadipocytes, the mechanisms by which sex hormones regulate adipose tissue are not fully understood. Females with androgen excess due to polycystic ovarian syndrome frequently exhibit central obesity, insulin resistance, hepatic steatosis, and other cardiometabolic risk factors, with similar adverse outcomes that can be seen in female-to-male transgender individuals receiving testosterone. Congenital adrenal hyperplasia (CAH) due to 21- hydroxylase deficiency is a condition in which both males and females are exposed to excess androgens as of the first trimester of pregnancy, and to varying degrees postnatally. One in 15,000 live births are affected with classical CAH, with universal newborn screening across the U.S. Significant adverse cardiometabolic outcomes can develop in early childhood and have been identified across the lifespan of CAH individuals, including obesity, early adiposity rebound, hypertension, and insulin resistance. Yet, there is currently little in the way of targeted treatment of cardiometabolic risk factors in CAH. The goal of this proposal is to non- invasively delineate androgen effects on adipose depots and ectopic fat by magnetic resonance (MR)- based imaging techniques. We propose to perform secondary analyses on imaging studies performed in the PI’s K23 award. With MR imaging (MRI), we will quantify regional adipose tissue distribution (abdominal visceral and subcutaneous, and gluteal-femoral) and liver fat, using Dixon quantitative chemical shift imaging. With proton (1H) MR spectroscopy (MRS), we will examine differences in triglyceride composition (saturated and unsaturated fatty acids) in abdominal and gluteal-femoral adipose depots, and determine intra- and extramyocellular lipid content. We hypothesize that we will find an androgen-related, central lipid distribution (increased abdominal vs. gluteal-femoral), with more saturated fatty acids in abdominal fat, in CAH youth. We also expect to find increased ectopic fat, and an association with excess androgens, in CAH. We predict a lack of sex differences in CAH youth, in contrast to sex-matched controls. The specific aims are to: 1) evaluate abdominal and gluteal-femoral adipose depots for lipid distribution and composition, non-invasively, by MRI and MRS in CAH youth vs. controls; 2) evaluate ectopic lipid content in liver by MRI and muscle by MRS in CAH youth vs. controls. This study of a human model of androgen excess can help to better understand androgen-driven effects on lipid distribution and metabolic risk in both sexes, and may inform targeted treatments to improve lipid deposition and insulin sensitivity in CAH. The project supports a priority area of the NICHD Pediatric Growth and Nutrition Branch: the hormonal regulation of adipose tissue.