The power of the Heterogenous Stock rat founder strains in modeling metabolic disease

Authors

Valerie A. Wagner, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
Katie L. Holl, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
Karen C. Clark, Cardiovascular Center, Medical College of Wisconsin, Milwaukee, WI.Follow
John J. Reho, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
Hans-Joachim Lehmler, Department of Occupational and Environmental Health, University of Iowa, Iowa City, IA.
Kai Wang, Department of Biostatistics, University of Iowa, Iowa City, IA.
Justin L. Grobe, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
Melinda R. Dwinell, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.
Hershel Raff, Advocate Aurora Health
Anne E. Kwitek, Department of Physiology, Medical College of Wisconsin, Milwaukee, WI.

Recommended Citation

Wagner VA, Holl KL, Clark KC, et al. The Power of the Heterogeneous Stock Rat Founder Strains in Modeling Metabolic Disease. Endocrinology. 2023;164(12):bqad157. doi:10.1210/endocr/bqad157

Affiliations

Aurora St. Luke's Medical Center, Advocate Aurora Research Institute

Abstract

Metabolic diseases are a host of complex conditions, including obesity, diabetes mellitus, and metabolic syndrome. Endocrine control systems (e.g., adrenals, thyroid, gonads) are causally linked to metabolic health outcomes. N/NIH Heterogeneous Stock (HS) rats are a genetically heterogeneous outbred population developed for genetic studies of complex traits. Genetic mapping studies in adult HS rats identified loci associated with cardiometabolic risks, such as glucose intolerance, insulin resistance, and increased BMI. This study determined underappreciated metabolic health traits and the associated endocrine glands within available substrains of the HS rat founders. We hypothesize that the genetic diversity of the HS rat founder strains causes a range of endocrine health conditions contributing to the diversity of cardiometabolic disease risks. ACI/EurMcwi, BN/NHsdMcwi, BUF/MnaMcwi, F344/StmMcwi, M520/NRrrcMcwi, and WKY/NCrl rats of both sexes were studied from birth until 13 weeks-of-age. Birth weight was recorded, body weight was measured weekly, metabolic characteristics were assessed, and blood and tissues were collected. Our data show wide variation in endocrine traits and metabolic health states in ACI, BN, BUF, F344, M520, and WKY rat strains. This is the first report to compare birth weight, resting metabolic rate, endocrine gland weight, hypothalamic-pituitary-thyroid axis hormones, and brown adipose tissue weight in these rat strains. Importantly, this work unveils new potential for the HS rat population to model early life adversity and adrenal and thyroid pathophysiology. The HS population likely inherited risk alleles for these strain-specific traits, making the HS rat a powerful model to investigate interventions on endocrine and metabolic health.

Document Type

Article

PubMed ID

37882530