No abstract

Background: Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acids transport into mitochondria via deletion of acetyl-CoA carboxylase 2 (ACC2) does not cause cardiomyopathy in non-obese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity induced cardiomyopathy, and if so, to elucidate the underlying mechanisms. Methods: We induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen inducible model (ACC2 iKO). Control (Con) and ACC2 iKO mice were subjected to high fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function and mitophagy activity were examined. Results: Despite both Con and ACC2 iKO mice exhibiting similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD induced cardiac dysfunction, pathological remodeling as well as mitochondria dysfunction. Similarly, increasing FAO by knock down of ACC2 prevented palmitate induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was partially attenuated in ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD induced downregulation of parkin. During stimulation for mitophagy, mitochondria localized parkin was severely reduced in Con HFD-fed mouse heart, which was partially restored in ACC2 iKO HFD-fed mice. Conclusions: These data show that increasing cardiac FAO alone does not cause cardiac dysfunction but protect against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD induced obesity is mediated, in part, by maintenance of mitochondria function through regulating parkin mediated mitophagy. Our findings also suggest that targeting the parkin dependent mitophagy pathway could be an effective strategy against the development of obesity induced cardiomyopathy.

Atopic cough, asthmatic cough consisting of cough variant asthma and cough predominant asthma, and SBS are major causes of chronic cough in Japan.

Body temperature homoeostasis in mammals is governed centrally through the regulation of shivering and non-shivering thermogenesis and cutaneous vasomotion. Non-shivering thermogenesis in brown adipose tissue (BAT) is mediated by sympathetic activation, followed by PGC-1α induction, which drives UCP1. Here we identify nardilysin (Nrd1 and NRDc) as a critical regulator of body temperature homoeostasis. Nrd1−/− mice show increased energy expenditure owing to enhanced BAT thermogenesis and hyperactivity. Despite these findings, Nrd1−/− mice show hypothermia and cold intolerance that are attributed to the lowered set point of body temperature, poor insulation and impaired cold-induced thermogenesis. Induction of β3-adrenergic receptor, PGC-1α and UCP1 in response to cold is severely impaired in the absence of NRDc. At the molecular level, NRDc and PGC-1α interact and co-localize at the UCP1 enhancer, where NRDc represses PGC-1α activity. These findings reveal a novel nuclear function of NRDc and provide important insights into the mechanism of thermoregulation.

NRDC is a promising biomarker for the early detection of ACS, even in UA patients without elevation of necrosis markers.