Abstract
Key metabolic hormones, such as insulin, leptin, and adiponectin, have been studied extensively in obesity, however the pathophysiologic relevance of the calcitonin family of peptides remains unclear. This family includes calcitonin (CT), its precursor procalcitonin (PCT), and alpha calcitonin-gene related peptide (αCGRP), which are all encoded by the gene Calca. Here, we studied the role of Calca-derived peptides in diet-induced obesity (DIO) by challenging Calcr−/− (encoding the calcitonin receptor, CTR), Calca−/−, and αCGRP−/− mice and their respective littermates with high-fat diet (HFD) feeding for 16 weeks. HFD-induced pathologies were assessed by glucose tolerance, plasma cytokine and lipid markers, expression studies and histology. We found that DIO in mice lacking the CTR resulted in impaired glucose tolerance, features of enhanced nonalcoholic steatohepatitis (NASH) and adipose tissue inflammation compared to wildtype littermates. Furthermore, CTR-deficient mice were characterized by dyslipidemia and elevated HDL levels. In contrast, mice lacking Calca were protected from DIO, NASH and adipose tissue inflammation, and displayed improved glucose tolerance. Mice exclusively lacking αCGRP displayed a significantly less improved DIO phenotype compared to Calca-deficient mice. In summary, we demonstrate that the CT/CTR axis is involved in regulating plasma cholesterol levels while Calca, presumably through PCT, seems to have a detrimental effect in the context of metabolic disease. Our study provides the first comparative analyses of the roles of Calca-derived peptides and the CTR in metabolic disease.
Highlights
It is well established that obesity is linked to components of the metabolic syndrome including insulin resistance, dyslipidemia and a low-grade pro-inflammatory state [1,2,3,4]
Analyses of organ weights at the end of the study revealed no alteration in the weights of liver and epididymal white adipose tissue (WAT) (Fig 1b)
We found that genetic inactivation of the CTR in diet-induced obesity (DIO) results in impaired glucose tolerance, features of enhanced nonalcoholic steatohepatitis (NASH) and adipose tissue inflammation
Summary
It is well established that obesity is linked to components of the metabolic syndrome including insulin resistance, dyslipidemia and a low-grade pro-inflammatory state [1,2,3,4]. In the investigation of molecules that may be involved in the regulation of metabolic health in obesity, there is still uncertainty regarding the roles of several circulating hormones such as the calcitonin family of peptides These include calcitonin (CT) and its precursor procalcitonin (PCT), as well as calcitonin-gene related peptide (αCGRP) all of which are encoded by the Calca gene in mice and have been linked to metabolic regulation in mice and humans. The primary transcript of the Calca gene is subjected to extensive post-transcriptional and post-translational modifications It is processed into two different mRNAs by alternative splicing, resulting in the synthesis of αCGRP in the central and peripheral nervous system, and PCT in the thyroid gland [7]. Systemic inflammation as observed in sepsis annihilates tissue specificity and results in ubiquitous Calca expression, leading to PCT release from many cell types, including adipocytes and hepatocytes [8,9]
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