Cardiac natriuretic peptides (NP) have been shown to control energy homeostasis. Epidemiological studies have shown that low level of plasma NP predict future development of type 2 diabetes (T2D). We have also observed a reduced expression of the biologically active NP receptor GCA of about 50% in metabolic tissues of obese humans and mice. The purpose of this study was to demonstrate that NP deficiency causes T2D in mice. GCA+/- and atrial NP-/- (ANP) mice and their wild type (WT) littermates were studied under normal chow and high fat diet for 12 weeks. GCA+/- and ANP-/- mice exhibit signs of systemic insulin resistance and glucose intolerance when compared to their WT littermates. This metabolic phenotype is accompanied by skeletal muscle insulin resistance and reduced lipid oxidative capacity, without noticeable changes in inflammatory profile of liver and adipose tissues. Interestingly, we observed elevated levels of lipotoxic lipids in skeletal muscle along with reduced mitochondrial mass and respiratory chain complexes. Collectively, these data indicate that ANP/GCA deficiency causes T2D and that ANP contributes to long-term maintenance of insulin sensitivity.
C. Moro: None.