Transgenic mice overexpressing neuropeptide Y: An experimental model of metabolic and cardiovascular diseases

Neuropeptide Y (NPY) is an abundant neurotransmitter in the brain and sympathetic nervous system (SNS). Hypothalamic NPY is known to be a key player in food intake and energy expenditure. NPY’s role in cardiovascular regulation has also been shown. In humans, a Leucine 7 to Proline 7 single nucleotide polymorphism (p.L7P) in the signal peptide of the NPY gene has been associated with traits of metabolic syndrome. The p.L7P subjects also show increased stress-related release of NPY, which suggests that more NPY is produced and released from SNS. The main objective of this study was to create a novel mouse model with noradrenergic cell-targeted overexpression of NPY, and to characterize the metabolic and vascular phenotype of this model. The mouse model was named OE-NPY^DBH mouse. Overexpression of NPY in SNS and brain noradrenergic neurons led to increased adiposity without significant weight gain or increased food intake. The mice showed lipid accumulation in the liver at young age, which together with adiposity led to impaired glucose tolerance and hyperinsulinemia with age. The mice displayed stress-related increased mean arterial blood pressure, increased plasma levels of catecholamines and enhanced SNS activity measured by GDP binding activity to brown adipose tissue mitochondria. Sexual dimorphism in NPY secretion pattern in response to stress was also seen. In an experimental model of vascular injury, the OE-NPY^DBH mice developed more pronounced neointima formation compared with wildtype controls. These results together with the clinical data indicate that NPY in noradrenergic cells plays an important role in the pathogenesis of metabolic syndrome and related diseases. Furthermore, new insights on the role of the extrahypothalamic NPY in the process have been obtained. The OE-NPY^DBH model provides an important tool for further stress and metabolic syndrome-related studies.

Nocturnal Transcutaneous Carbon Dioxide and Early Changes in Atherosclerosis in Pre- and Postmenopausal Women

The risk of cardiovascular diseases and sleep-disordered breathing increases after menopause. This cross-sectional study focuses on overnight transcutaneous carbon dioxide (TcCO₂) measurements and their power to predict changes in the early markers of cardiovascular and metabolic diseases. The endothelial function of the brachial artery, the intima-media thickness of the carotid artery, blood pressure, glycosylated hemoglobin A1C and plasma levels of cholesterols and triglycerides were used as markers of cardiovascular and metabolic diseases. The study subjects consisted of healthy premenopausal women of 46 years of age and postmenopausal women of 56 years of age. From wakefulness to sleep, the TcCO₂ levels increased more in postmenopausal women than in premenopausal women. In estrogen-users the increase in TcCO₂ levels was even more pronounced than in other postmenopausal women. From the dynamic behaviour of the nocturnal TcCO₂ signal, several important features were detected. These TcCO₂ features had a remarkable role in the prediction of endothelial dysfunction and thickening of the carotid wall in healthy premenopausal women. In addition, these TcCO₂ features were linked with blood pressure, lipid profile and glucose balance in postmenopausal women. The nocturnal TcCO₂ profile seems to contain significant information, which is associated with early changes in cardiovascular diseases in middle-aged women. TcCO₂ might not only measure the tissue carbon dioxide levels, but the TcCO₂ signal variation may also reflect peripheral vasodynamic events caused by increased sympathetic activity during sleep.

Molecular patterns behind immunological and metabolic alterations in lysinuric protein intolerance

Lysinuric protein intolerance (LPI) is a recessively inherited disorder characterised by reduced plasma and increased urinary levels of cationic amino acids (CAAs), protein malnutrition, growth failure and hyperlipidemia. Some patients develop severe immunological, renal and pulmonary complications. All Finnish patients share the same LPIFin mutation in the SLC7A7 gene that encodes CAA transporter y+LAT1. The aim of this study was to examine molecular factors contributing to the various symptoms, systemic metabolic and lipid profiles, and innate immune responses in LPI. The transcriptomes, metabolomes and lipidomes were analysed in whole-blood cells and plasma using RNA microarrays and gas or liquid chromatography-mass spectrometry techniques, respectively. Toll-like receptor (TLR) signalling in monocyte-derived macrophages exposed to pathogens was scrutinised using qRT-PCR and the Luminex technology. Altered levels of transcripts participating in amino acid transport, immune responses, apoptosis and pathways of hepatic and renal metabolism were identified in the LPI whole-blood cells. The patients had increased non-essential amino acid, triacylglycerol and fatty acid levels, and decreased plasma levels of phosphatidylcholines and practically all essential amino acids. In addition, elevated plasma levels of eight metabolites, long-chain triacylglycerols, two chemoattractant chemokines and nitric oxide correlated with the reduced glomerular function in the patients with kidney disease. Accordingly, it can be hypothesised that the patients have increased autophagy, inflammation, oxidative stress and apoptosis, leading to hepatic steatosis, uremic toxicity and altered intestinal microbe metabolism. Furthermore, the LPI macrophages showed disruption in the TLR2/1, TLR4 and TLR9 pathways, suggesting innate immune dysfunctions with an excessive response to bacterial infections but a deficient viral DNA response.