Friday, January 30, 2009


Neuronal CaSRs regulate general growth, skeletal development, and energy homeostasis

"To assess biological functions of neuronal CaSR in vivo we generated mice with CaSR knockout (KO) targeted to neurons. The KO mice were viable but growth-retarded with smaller undermineralized skeleton. These growth and skeletal defects were associated with dysregulation of hypothalamus (Hyp)–pituitary gland (Pit)–GH/IGF1 axis in the KO mice, reflected by decreased serum GH and IGF1 levels and reduced GH and GHRH RNA levels in their Pit and Hyp, respectively. Genomic analyses confirmed that CaSR gene excision didn't occur in liver, cartilage, and bones and Western blotting showed intact CaSR expression in the Pit of the KO mice, supporting the primary effects of CaSR KO in Hyp neurons on the growth defects. In the KO mice, the expression of TSH, ACTH, FSH, and LH RNA in their Pit and expression of TRH and GnRH in their Hyp were also decreased by 35–60%. These data together indicate that CaSR KO caused general dysregulation of Hyp functions and produced a panhypopituitarism in the KO mice. Furthermore, in the Hyp of KO mice, expressions of agouti-related protein and neuropeptide Y, which enhance feeding and decrease energy expenditure, were increased by 70 and 25%, respectively, while pro-opiomelanocortin, which suppresses feeding and increases energy expenditure, was decreased by ≈ 30%. These changes in gene expression were accompanied by increased body fat and glucose-intolerance despite their elevated serum leptin levels, suggesting increased leptin-resistance in the KO mice. Together, our data support a critical role for neuronal CaSRs in the integration of general growth, skeletal development, and energy homeostasis."

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