Sex-biased role of H19X non-coding RNAs in regulating fat mass
Authors: Ji Xuan , Yuan Fei , Lin Hsiang Chi , Zou Joy , Chen Jiayi , Park Yoonjung , Kumar Ashok , Liu Yu 
Published: May 2023

Background: Fat mass regulation is widely studied but how non-coding RNAs contribute to the process is less understood. H19X is a cluster of ncRNAs encoded by a locus in Xq26.3 and has diverse roles in regulating cell differentiation, proliferation, plasticity and metabolism. We previously showed that it caused anabolic resistance in skeletal muscle. Recent analysis in human fat samples showed differential expression of H19X in obese vs. non-obese individuals. So, we hypothesized that H19X exert anti-anabolism effect in fat. Objective: To establish a role of H19X in regulating fat mass, and address if the effect is sex biased. Methods: All animal procedures have been approved by University of Houston IACUC. In female mice, comparison is among wild type (wt), heterozygous (het) and homozygous knockouts (mt). In male mice, comparison is between wt and hemizygous knockouts (hem). The mice were fed with high fat diet (HFD) (60%) at 5 months old for 4 months. Body weight and composition were measured via EchoMRI. The Mice were monitored in Phenomaster for O2 consumption (VO2), CO2 production (VCO2), Respiratory Exchange Rate (RER) and heat production (H). Subcutaneous WAT (sWAT), epididymal WAT (eWAT), retroperitoneal WAT (rpWAT) and interscapular BAT (iBAT) were collected for molecular and histological analyses. Results: In female mice, het gained more weight than wt (51.63 % vs. 28.58 %). The final body weight of het (48.27 ± 13.11 g) was significantly higher (P = 0.0194) than wt (33.74 ± 5.5 g). Relative fat mass in het (47.41 ± 13.41%) was higher than wt (33.57 ± 10.14%) and relative lean mass in het (46.29 ± 11.52 %) was lower than wt (59.47 ± 9.13 %). The weight of all fat types in het (sWAT, 0.88 + 0.46 g; eWAT, 2.50 ± 1.44 g; rpWAT, 0.54 ± 0.34 g; iBAT, 0.095 ± 0.018 g) were higher than wt (sWAT, 0.41 ± 0.22 g; eWAT, 1.17 ± 0.75 g; rpWAT, 0.28 ± 0.21 g; iBAT, 0.055 ± 0.019 g). iBAT in het was significantly heavier (P = 0.0055) and evidently whitening; Some brown adipocytes in het were enlarged and resembled unilocular white adipocytes. The het (VO2, 3269.99 ± 601.03 ml/h/kg; VCO2, 2366.91 ± 410.73 ml/h/kg and H, 15.51 ± 2.82 kcal/h/kg) showed significantly lower (P < 0.01) metabolic performance than wt (VO2, 4277.36 ± 583.23 ml/h/kg; VCO2, 3130.87 ± 481.39 ml/h/kg; H, 20.32 ± 2.81 kcal/h/kg), except RER, supporting that H19X is pro-catabolic/anti-anabolic in main metabolic tissues. Molecular analysis identified FASN and G0S2 as targets of H19X, suggesting reciprocal regulation over fatty acid synthesis and lipolysis. The bigger and heavier fat tissues in hem were the only differences between male mice. So, fat deposition is less remarkable in male hem mice. Conclusions: H19X deficiency influences female and male mice in body weight, body composition and metabolism to different extents. Female showed severer HFD induced obesity than male. The mechanism for the sex difference is unclear; dose effects and differential hormonal regulations may be involved. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.