Hypogonadism, adipose tissue inflammation, and adipose tissue circadian clock disruption promote metabolic dysfunction in Klinefelter syndrome

Sex chromosome aneuploidies like Klinefelter syndrome (KS) represent a naturally occurring genetic model to investigate metabolic function at the intersection of sex chromosomes, hypogonadism and sex hormone replacement therapy. Men with KS have severe metabolic dysfunction and a more than 2.5-fold increased risk of type 2 diabetes. We assessed body composition, insulin sensitivity, and adipokine profile before and after testosterone replacement therapy (TRT) in KS. TRT does not completely normalize body composition or abolish insulin resistance in KS, indicating insufficient rescue of metabolic risk by correction of hypogonadism. We then assessed gene expression in KS adipose tissue related to the metabolic profile, demonstrating that hypogonadism independently increased adipose tissue expansion and inflammation in KS, and profound disruption of adipose tissue circadian rhythm tightly associated with insulin resistance and signs of biological aging in adipose tissue. We further provide a prediction model for body fat in KS. Our data reveals intricate interactions between sex and metabolism, evolving the pathophysiological understanding of KS.