Female-Specific Features of Metabolic Syndrome in an LH Congenic Rat. FASEB J 2022 May;36 Suppl 1
Date
05/14/2022Pubmed ID
35555071DOI
10.1096/fasebj.2022.36.S1.R3862Scopus ID
2-s2.0-85130021782 (requires institutional sign-in at Scopus site)Abstract
Central obesity, high blood pressure, dyslipidemia, and insulin resistance are a collection of cardiovascular and metabolic risk factors that form the basis of the Metabolic Syndrome (MetS) and represent a major public health burden worldwide. The phenotypes that define MetS are all highly heritable, but their genetic complexity necessitates the use of animal models to tease apart novel pathways. The Lyon Hypertensive (LH) rat is a well-characterized model of MetS, exhibiting spontaneous and profound differences in features of MetS compared to its metabolically healthy control, the Lyon Normotensive (LN) rat. To understand the genomic causes of MetS in the LH rat, we developed a congenic rat model, where a portion of LN chromosome 17 is introgressed on the LH genomic background. Our hypothesis was that differences in metabolic features between the LH controls and the congenic rats (LH17LNa) would be due to the replaced region of the genome. Male and female LH17LNa rats and LH controls were phenotyped for a variety of MetS characteristics, including weekly body growth until tissue collection at 15 weeks of age, body composition by nuclear magnetic resonance (NMR) at 8, 11, and 14 weeks of age, metabolic rate (Promethion system) between 10 and 12 weeks of age, and adipose tissue collection and histological examination. We observed a significant decrease in total body growth in female congenics, beginning at 12 weeks of age and persisting throughout the rest of the study. Prior to the divergence in body weight, female congenics showed significant increases in fat mass and significant decreases in fat free mass that remained consistent at all timepoints measured. We also found significant female-specific decreases in metabolic rate. Tissue collection revealed the source of the increased adiposity in the female LH17LNa rats was specific to abdominal white adipose tissue, and this phenomenon was further explained by significant hypertrophy in those adipocytes, with no evidence of adipocyte hyperplasia. Genome resequencing of the parental strains identified a nonsense mutation in Ercc6l2, implicating this gene as a strong contender underlying the phenotype differences in the congenics. Ercc6l2 is a helicase involved in transcription-coupled DNA repair, which is specifically mobilized to repair oxidative stress-induced DNA damage in post-mitotic cells. Truncating mutations in Ercc6l2 have previously been implicated in genome instability and premature aging in hematopoetic stem cells in patients with bone marrow failure. The discovery of the significance of Ercc6l2 in the context of female-specific adipocyte biology could represent a novel role of DNA repair syndromes in MetS pathogenesis.
Author List
Clark KC, Wagner VA, Holl KL, Reho JJ, Grobe JL, Kwitek AEAuthor
John J. Reho Research Scientist II in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsBlood Pressure
DNA Helicases
Female
Humans
Hypertension
Male
Metabolic Syndrome
Obesity
Phenotype
Rats
