Abstract
Mice with somatotrope-specific deletion of the Janus kinase binding site in leptin receptors are GH deficient as young adults and become obese by 6 months of age. This study focused on the metabolic status of young (3-4.5 month old) preobese mutant mice. These mutants had normal body weights, lean body mass, serum leptin, glucose, and triglycerides. Mutant males and females showed significantly higher respiratory quotients (RQ) and lower energy output, resulting from a higher volume of CO(2) output and lower volume of O(2) consumption. Deletion mutant females were significantly less active than controls; they had higher levels of total serum ghrelin and ate more food. Mutant females also had lower serum insulin and higher glucagon. In contrast, deletion mutant males were not hyperphagic, but they were more active and spent less time sleeping. Adiponectin and resistin, both products of adipocytes, were increased in male and female mutant mice. In addition, mutant males showed an increase in circulating levels of the potent lipogenic hormone, glucose-dependent insulinotropic peptide. Taken together, these results indicate that mutant mice may become obese due to a reduction in lipid oxidation and energy expenditure. This may stem from GH deficiency. Reduced fat oxidation and enhanced insulin sensitivity (in females) are directly related to GH deficiency in mutant mice because GH has been shown by others to increase insulin sensitivity and fat oxidation and reduce carbohydrate oxidation. Gender-dependent alterations in metabolic signals may further exacerbate the future obese phenotype and affect the timing of its onset. Females show a delay in onset of obesity, perhaps because of their low serum insulin, which is lipogenic, whereas young males already have higher levels of the lipogenic hormone, glucose-dependent insulinotropic peptide. These findings signify that leptin signals to somatotropes are vital for the normal metabolic activity needed to optimize body composition.
Highlights
MethodsProduction of deletion mutant mice lacking leptin receptor (LEPR) exon 17 in somatotropesBreeding cages were set up to produce N6 and N7 generation deletion mutants and littermate controls (FVB/NJ) as previously described [22]
We calculated lean body mass, which was body weight (M) to the 3⁄4 power, according to Kleiber’s law [26, 27]. This formula is a wellestablished surrogate for metabolic mass. Their weight was loaded into the comprehensive laboratory animal monitoring system (CLAMS) program and the conversion to lean body mass was built into the software used by the CLAMS, which normalized the volume of oxygen, carbon dioxide, and the resulting respiratory quotient (RQ) to lean body mass
The strongest predisposition to obesity was seen in the calculation of respiratory quotients (RQ ϭ CO2 production (VCO2)/VO2) for these mutants
Summary
Production of deletion mutant mice lacking LEPR exon 17 in somatotropesBreeding cages were set up to produce N6 and N7 generation deletion mutants and littermate controls (FVB/NJ) as previously described [22]. Comprehensive laboratory animal monitoring system The indirect calorimetry, activity levels, and food intake were determined using the Oxymax CLAMS (Columbus Instruments, Columbus, OH) over a period of 72 h. This unit is in the same room that houses the breeding colonies, which facilitates acclimation. We calculated lean body mass, which was body weight (M) to the 3⁄4 power, according to Kleiber’s law [26, 27]. This formula is a wellestablished surrogate for metabolic mass. Their weight was loaded into the CLAMS program and the conversion to lean body mass was built into the software used by the CLAMS, which normalized the volume of oxygen, carbon dioxide, and the resulting respiratory quotient (RQ) to lean body mass
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