A novel compound heterozygous leptin receptor mutation causes more severe obesity than in Leprdb/db mice

Journal of Lipid Research

Sebastian Dommel¹  Tina Heiland²  Matthias Blüher³  Nora Klöting⁴  Peter Kovacs⁴  Claudia Berger⁵  Esther Guiu-Jurado⁵  Steffen Roßner⁵  Henrike O. Heyne⁶  Jana Lorenz⁷  Corinna Höfling⁷  Michael Dannemann⁷  Janet Kelso⁸ 

[1] Broad Institute of Harvard and MIT, Cambridge, MA, USA;Institute for Molecular Medicine Finland: FIMM, Helsinki, Finland;Institute of Genomics, University of Tartu, Tartu, Estonia;Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany;Medical Department III, Endocrinology, Nephrology, Rheumatology, CRC1052, University of Leipzig Medical Center, Leipzig, Germany;Medical Department, Institute for Human Genetics, University of Leipzig Medical Center, Leipzig, Germany;Medical Department, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University of Leipzig Medical Center, Leipzig, Germany;Paul-Flechsig-Institute for Brain Research, University of Leipzig, Leipzig, Germany;

关键词: Lepr;    leptin receptor mutation;    obesity;    compound heterozygous;    genetic background;   

DOI  :  

来源: DOAJ

【 摘 要 】

The leptin receptor (Lepr) pathway is important for food intake regulation, energy expenditure, and body weight. Mutations in leptin and the Lepr have been shown to cause early-onset severe obesity in mice and humans. In studies with C57BL/6NCrl mice, we found a mouse with extreme obesity. To identify a putative spontaneous new form of monogenic obesity, we performed backcross studies with this mouse followed by a quantitative trait locus (QTL) analysis and sequencing of the selected chromosomal QTL region. We thereby identified a novel Lepr mutation (C57BL/6N-LeprL536Hfs*6-1NKB), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, LeprL536Hfs*6 develop early onset obesity and their body weight exceeds that of Leprdb/db mice at an age of 30 weeks. Similar to Leprdb/db mice, the LeprL536Hfs*6 model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Leprdb/wt with LeprL536Hfs*6/wt mice results in compound heterozygous LeprL536Hfs*6/db mice, which develop even higher body weight and fat mass than both homozygous Leprdb/db and LeprL536Hfs*6 mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.

【 授权许可】

Unknown