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.