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

Claudia Berger; Henrike O Heyne; Tina Heiland; Sebastian Dommel; Corinna Höfling; Esther Guiu-Jurado; Jana Lorenz; Steffen Roßner; Michael Dannemann; Janet Kelso; Peter Kovacs; Matthias Blüher; Nora Klöting

doi:10.1016/j.jlr.2021.100105

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

J Lipid Res. 2021:62:100105. doi: 10.1016/j.jlr.2021.100105. Epub 2021 Aug 11.

Authors

Affiliations

¹ Medical Department III, Endocrinology, Nephrology, Rheumatology, CRC1052, University of Leipzig Medical Center, Leipzig, Germany.
² Medical Department, Institute for Human Genetics, University of Leipzig Medical Center, Leipzig, Germany; Institute for Molecular Medicine Finland: FIMM, Helsinki, Finland; Broad Institute of Harvard and MIT, Cambridge, MA, USA.
³ Medical Department, Neurology and Dermatology, Division of Gastroenterology and Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
⁴ Paul-Flechsig-Institute for Brain Research, University of Leipzig, Leipzig, Germany.
⁵ Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany; Institute of Genomics, University of Tartu, Tartu, Estonia.
⁶ Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
⁷ Medical Department III, Endocrinology, Nephrology, Rheumatology, CRC1052, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany.
⁸ Medical Department III, Endocrinology, Nephrology, Rheumatology, CRC1052, University of Leipzig Medical Center, Leipzig, Germany; Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig, Leipzig, Germany. Electronic address: nora.kloeting@helmholtz-muenchen.de.

Abstract

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-Lepr^L536Hfs*^6-1NKB), which is located at chromosome 4, exon 11 within the CRH2-leptin-binding site. Compared with C57BL/6N mice, Lepr^L536Hfs*⁶ develop early onset obesity and their body weight exceeds that of Lepr^db/db mice at an age of 30 weeks. Similar to Lepr^db/db mice, the Lepr^L536Hfs*⁶ model is characterized by hyperphagia, obesity, lower energy expenditure and activity, hyperglycemia, and hyperinsulinemia compared with C57BL/6N mice. Crossing Lepr^db/wt with Lepr^L536Hfs*^6/wt mice results in compound heterozygous Lepr^L536Hfs*^6/db mice, which develop even higher body weight and fat mass than both homozygous Lepr^db/db and Lepr^L536Hfs*⁶ mice. Compound heterozygous Lepr deficiency affecting functionally different regions of the Lepr causes more severe obesity than the parental homozygous mutations.

Keywords: Lepr; compound heterozygous; genetic background; leptin receptor mutation; obesity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Mice
Mice, Inbred C57BL
Mice, Obese
Mice, Transgenic
Mutation
Obesity / genetics*
Receptors, Leptin / genetics*

Substances

Receptors, Leptin
leptin receptor, mouse