Abstract
Calcitonin (CT) plays an important role in calcium homeostasis, and its precursor, proCT, is positively associated with the body mass index in the general human population. However, the physiological role of endogenous CT in the regulation of metabolism remains unclear. Knockout mice with gene-targeted deletion of exon 4 of Calca (CT KO) were generated by targeted modification in embryonic stem cells. Male mice were used in all experiments and were fed a slightly higher fat diet than the standard diet. The CT KO mice did not exhibit any abnormal findings in appearance, but exhibited weight loss from 15 months old, i.e., significantly decreased liver, adipose tissue, and kidney weights, compared with wild-type control mice. Furthermore, CT KO mice exhibited significantly decreased fat contents in the liver, lipid droplets in adipose tissues, serum glucose, and lipid levels, and significantly increased insulin sensitivity and serum adiponectin levels. CT significantly promoted 3T3-L1 adipocyte differentiation and suppressed adiponectin release. These results suggested that CT gene deletion prevents obesity, hyperglycemia, and hyperlipidemia in aged male mice. This is the first definitive evidence that CT may contribute to glucose and lipid metabolism in aged male mice, possibly via decreased adiponectin secretion from adipocytes.
Highlights
Calcitonin (CT) is produced by thyroid C-cells and plays an important role in calcium homeostasis[1]
Some reports have shown that αCGRP knock out (KO) mice are protected from diet-induced obesity via regulation of lipid metabolism and energy homeostasis[7,8,9]
We generated CT KO mice, in which Calca was modified so that CT was not expressed but αCGRP expression remained. These KO mice showed weight loss in old age, and decreased liver and adipose tissue weights compared with the age-matched WT controls
Summary
Calcitonin (CT) is produced by thyroid C-cells and plays an important role in calcium homeostasis[1]. Some reports have shown that αCGRP knock out (KO) mice are protected from diet-induced obesity via regulation of lipid metabolism and energy homeostasis[7,8,9]. Bartelt et al reported that mice lacking Calca, which encodes CT and αCGRP, are protected from diet-induced obesity, www.nature.com/scientificreports/. Some reports have shown that a therapeutic dose of CT decreases levels of lipids containing cholesterol and triglyceride, improves energy and glucose homeostasis, and protects against obesity in rats[11,12,13]. Higher CT levels in obese humans have been reported[14] These results suggested that the CT family of peptides regulates lipid and glucose metabolism. To clarify the role of CT in body weight regulation, we investigated phenotypic alterations in CT KO mice, in which Calca was modified to knock out CT expression while retaining normal αCGRP expression
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