Phenotype of fatty Due to Gln269Pro Mutation in the Leptin Receptor (Lepr)

Abstract

The rat fatty (fa) mutation produces profound obesity of early onset caused by hyperphagia, defective nonshivering thermogenesis, and preferential deposition of energy into adipose tissue. Genetic mapping studies indicate that fa and diabetes (db) are homologous loci in the rat and mouse genomes, respectively. It has been shown that db alleles carry mutations in the Lepr (leptin receptor) gene. This paper describes a point mutation in the fatty allele of Lepr. A nucleotide substitution at position 880 (A-->C) causes an amino acid substitution at position 269 (Gln-->Pro). The mutation generates a novel Msp I site that cosegregates with fa in 1,028 meioses examined in obese F2 progeny from two crosses (Bnx13M and WKYx13M) and is still segregating in three rat colonies. PCR-based mutagenesis was used to introduce the fa mutation into the mouse Lepr cDNA. Transient transfection studies indicate that the mutant Lepr cDNA has greatly reduced binding of leptin (Lep) at the cell surface. These data are strong evidence that the single nucleotide substitution in the fa allele of Lepr (Leprfa) is responsible for the obese phenotype.

Leptin Resistance in Vagal Afferent Neurons Inhibits Cholecystokinin Signaling and Satiation in Diet Induced Obese Rats

“…Zucker rats are a genetic model of leptin receptor deficiency [25], [26]. As previously reported, homozygous Zucker rats (LepR fa /LepR fa ), weighed significantly more than lean Zucker rats when fed on chow (p<0.01; Fig.…”

“…Zucker rats are completely insensitive to leptin as a result of a single amino acid substitution of a glutamine for a proline in the leptin receptor gene (Ob-R) [ 25 ], [ 29 ]. Zucker rats homozygous for the fa gene are morbidly obese and characterized by fat cell hypertrophy and hyperplasia [30], increased adipose tissue, lipoprotein lipase activity [31], hyperinsulinemia, hypertriglyceridemia, and hyperphagia [32] compared to their lean heterozygous counterparts.…”

Sleep and obesity: A focus on animal models

“…These animals are homozygous for the fatty (fa/fa) allele, have a mutation in the leptin receptor, and are obese and exhibit characteristics of human metabolic syndrome (Aleixandre de Artinano and Miguel Castro, 2009; Zucker, 1961). They become noticeably obese by the 3 rd to 5 th week after birth (Aleixandre de Artinano and Miguel Castro, 2009) and exhibit hyperphagia (Chua et al, 1996b). Food restriction normalizes body weight without affecting body composition and excessive body fat persists in these animals (Cleary et al, 1980).…”

Effects of high-fat diet and fructose-rich diet on obesity, dyslipidemia and hyperglycemia in the WBN/Kob-<i>Lepr^fa</i> rat, a new model of type 2 diabetes mellitus

“…The leptin receptor fatty gene ( Lepr fa ) is a recessive mutation that leads to leptin receptor deficiency, and homozygous animals ( fa/fa ) exhibit obesity and hyperphagia, in addition to insulin resistance and glucose intolerance [6]. Previous reports demonstrated that WBKDF rats have severe obesity and insulin resistance, both of which lead to developing T2DM [1, 11, 15, 16].…”