SHBG-C57BL/ksJ-db/db: A New Mouse Model to Study SHBG Expression and Regulation During Obesity Development

• Published in: Endocrinology (Philadelphia) Vol. 156; no. 12; pp. 4571 - 4581
• Main Authors: Saéz-López, Cristina, Rivera-Giménez, Marta, Hernández, Cristina, Simó, Rafael, Selva, David M.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.12.2015
• Subjects: Adult; Animal models; Animals; Biomarkers; Biopsy; Body weight; Body weight gain; Cardiovascular diseases; Diabetes; Diabetes mellitus (non-insulin dependent); Disease Models, Animal; Down-regulation; Fatty liver; Female; Gene Expression Regulation; Gene regulation; Globulins; Health risks; Hepatocyte Nuclear Factor 4 - genetics; Hepatocyte Nuclear Factor 4 - metabolism; Humans; In vivo methods and tests; Liver; Liver - metabolism; Liver diseases; Male; Metabolic disorders; Metabolic syndrome; Metabolism; Mice; Mice, Inbred C57BL; Mice, Transgenic; Middle Aged; Molecular modelling; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; Obesity; Obesity - genetics; Obesity - metabolism; Peroxisome proliferator-activated receptors; PPAR gamma - genetics; PPAR gamma - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Sex Hormone-Binding Globulin - genetics; Sex Hormone-Binding Globulin - metabolism; Sex hormones; Testosterone; Transcription factors; Transgenic mice
• ISSN: 0013-7227; 1945-7170; 1945-7170
• DOI: 10.1210/en.2015-1677

Low plasma sex hormone-binding globulin (SHBG) levels in overweight individuals are a biomarker for the metabolic syndrome and are predictive of type 2 diabetes and cardiovascular disease risk. There are no in vivo models to study SHBG expression and regulation during obesity development. The main reason for this is that the obesity-prone rodent models cannot be used to study this issue, because rodents, unlike humans, do not express the SHBG gene in their livers. We have developed a unique mouse model that expresses the human SHBG, and it develops obesity, by crossing the human SHBG transgenic mice with the C57BL/ksJ-db/db mice. The results obtained with the SHBG-C57BL/ksJ-db/db mouse model have allowed us to determine that the SHBG overexpression in the C57BL/ksJ-db/db reduced the body weight gain but did not change the metabolic profile of these mice. Moreover, we elucidated the molecular mechanisms and transcription factors causing the SHBG down-regulation during obesity development, which involved changes in liver hepatocyte nuclear factor 4α and peroxisome proliferator-activated receptor-γ mRNA and protein levels. Furthermore, these results were confirmed using human liver biopsies. Importantly, we also showed that this model resembles what occurs in human obese subjects, because plasma SHBG and total testosterone levels where reduced in obese mice when compared with lean mice. Future research using this unique mouse model will determine the role of SHBG in the development and progression of obesity, type 2 diabetes, or fatty liver disease.