Abstract
Lipedema is an often underdiagnosed chronic disorder that affects subcutaneous adipose tissue almost exclusively in women, which leads to disproportionate fat accumulation in the lower and upper body extremities. Common comorbidities include anxiety, depression, and pain. The correlation between mood disorder and subcutaneous fat deposition suggests the involvement of steroids metabolism and neurohormones signaling, however no clear association has been established so far. In this study, we report on a family with three patients affected by sex-limited autosomal dominant nonsyndromic lipedema. They had been screened by whole exome sequencing (WES) which led to the discovery of a missense variant p.(Leu213Gln) in AKR1C1, the gene encoding for an aldo-keto reductase catalyzing the reduction of progesterone to its inactive form, 20-α-hydroxyprogesterone. Comparative molecular dynamics simulations of the wild-type vs. variant enzyme, corroborated by a thorough structural and functional bioinformatic analysis, suggest a partial loss-of-function of the variant. This would result in a slower and less efficient reduction of progesterone to hydroxyprogesterone and an increased subcutaneous fat deposition in variant carriers. Overall, our results suggest that AKR1C1 is the first candidate gene associated with nonsyndromic lipedema.
Highlights
Lipedema is a chronic debilitating disorder affecting subcutaneous (SC) adipose tissue characterized by bilateral increased circumference of extremities, pain sensations, and bruising. It leads to a disproportionate body shape [1] with subcutaneous fat accumulation in the lower and upper extremities that can result in considerable disability
We argue in favor of the involvement of AKR1C1 in lipedema
We speculate that a partial loss of function in 20α-hydroxysteroid dehydrogenase (HSD) activity of AKR1C1 would result in diminished inactivation of allopregnanolone, that could still exert its analgesic effect
Summary
Lipedema is a chronic debilitating disorder affecting subcutaneous (SC) adipose tissue characterized by bilateral increased circumference of extremities, pain sensations, and bruising. Estradiol is important to mobilize adipose energetic reserve, and in the brain, it contributes to the regulation of body energy homeostasis [3,11], whereas, in rats, progesterone reverses the weight-reducing actions of estradiol [12,13] This suggests a differential type of regulation of the SC adipose tissue cells by different sex steroids. Growing evidence suggests that sex hormone-specific effects could be one of the key biological features for higher mood disease prevalence in women [14]. Neurosteroid hormones or their derivatives influence the regulation of the anxiety-related brain functions, thereby modulating individual anxiety states [14]. AKR1C1 (–122.91 ± 23.60 kJ/mol vs. –105.66 ± 23.88 kJ/mol) and NADP+
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