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Ablation of Leptin Signaling to Somatotropes: Changes in Metabolic Factors that Cause Obesity

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posted on 06.12.2013, 00:00 by Noor Akhter, Angela K. Odle, Melody L. Allensworth-James, Anessa C. Haney, Mohsin M. Syed, Michael A. Cozart, Streamson Chua, Rhonda Kineman, Gwen V. Childs
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 ofCO2 output and lower volume ofO2 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.




This work was supported by Grants National Institutes of Health (NIH) R03 HD059066 and NIH 1R01HD059056 (to G.V.C.) and core facilities funded by NIH Grants NCRR P20 RR020146 and NIH P30 NS047546 (at University of Arkansas for Medical Sciences), and NIH Grant P01 DK26687 (to S.C.), Department of Veterans Affairs, Office of Research and Development, Veterans Administration Merit Awards BX001114 and NIH grant RO1 DK088133 (to R.D.K.).


Publisher Statement

The original version is available through Endocrine Society at DOI: 10.1210/en.2012-1331.


Akhter, N. Odle, A. K. Allensworth-James, M. L. Haney, A. C. Syed, M. M. Cozart, M. A. Chua, S. Kineman, R. Childs, G. V. Ablation of Leptin Signaling to Somatotropes: Changes in Metabolic Factors that Cause Obesity. Endocrinology. Aug 3 2012. doi: 10.1210/en.2012-1331


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