👤 Deniz Atasoy

Alzheimer's disease (AD) is a multifactorial disorder that demands a comprehensive management strategy. Both aerobic exercise training and intermittent fasting (IF) have been shown to ameliorate AD symptoms, yet the impact of exercise in the fasted state remains understudied. This study compared the effects of four weeks of moderate‑intensity treadmill running in either a fasted or a normal fed state on cognitive function and hippocampal BDNF signaling in an amyloid-β (Aβ) Show less

The melanocortin receptor accessory protein 2 (MRAP2), which is abundantly expressed in the brain including the hypothalamus, has emerged as a key regulator of melanocortin-4 receptor (MC4R) activity. We sought to delineate the physiological significance of MRAP2 in MC4R neurons, with a particular focus on metabolic, autonomic and cardiovascular functions. Selective deletion of MRAP2 in MC4R neurons causes obesity that was associated with hyperphagia and impairment in glucose homeostasis and insulin sensitivity. MC4R agonist Melatonan II (MTII)-induced anorectic effects were blunted in mice lacking MRAP2 in MC4R neurons, whereas Celastrol retained its efficacy in reducing food intake and body weight. MRAP2 deletion also reduced baseline sympathetic nerve activity (SNA), particularly the SNA subserving the kidney. This was associated with reduced innervation of the kidney. In addition, MTII-induced increases in renal and brown adipose tissue (BAT) SNA as well as hepatic vagal nerve activity were significantly attenuated in MC4R neuron MRAP2-deficient mice. Transynaptic tracing revealed that MC4R neurons projecting to BAT and kidneys were localized to specific brain nuclei including the paraventricular nucleus of the hypothalamus, providing anatomical substrate for MRAP2 regulation of sympathetic outflow. Although the loss of MRAP2 in MC4R neurons did not affect arterial pressure, it caused a significant decrease in heart rate and baroreflex sensitivity. Finally, MRAP2 deficiency in MC4R neurons attenuated MTII-induced increase in arterial pressure and heart rate. These findings demonstrate that in addition to its role in energy balance and glucose homeostasis MRAP2 in MC4R neurons is crucial for cardiovascular autonomic regulation and is required for the development of obesity-associated hypertension and autonomic dysfunction. Show less

Subclinical atherosclerosis is a key predictor of cardiovascular events. While inflammation plays a crucial role in atherosclerosis, the involvement of Human Neutrophil Peptides 1-3 (HNP1-3) in its progression remains unclear. The study investigates the association of HNP1-3 and PCSK9 with coronary atherosclerotic burden and explores the potential mediatory role of PCSK9 in HNP1-3's effect on atherogenesis. Patients who underwent coronary computed tomographic angiography (CCTA) and had subclinical atherosclerosis (luminal stenosis < 50%) or normal coronary arteries were included in this cross-sectional study. HNP1-3 and PCSK9 levels were measured using ELISA, and coronary plaque burden was quantified using the modified Gensini score. Patients with subclinical atherosclerosis had significantly higher levels of HNP1-3 (p < 0.001), PCSK9 (p < 0.001), and lipoprotein(a) [Lp(a)] (p < 0.001) compared to controls. HNP1-3 was an independent predictor of subclinical atherosclerosis (p < 0.001), and its levels positively correlated with the modified Gensini score (p < 0.001). In multinomial logistic regression, higher levels of HNP1-3, PCSK9, and Lp(a) were independently associated with higher modified Gensini score tertiles. Mediation analysis revealed that PCSK9 mediated 48.7% of the effect of HNP1-3 on the modified Gensini score. After adjusting for hsCRP and cardiovascular risk factors, the direct effect of HNP1-3 became statistically insignificant, while the indirect effect via PCSK9 remained significant, suggesting that PCSK9 fully mediates the pro-atherogenic effects of HNP1-3. In conclusion, HNP1-3 is a novel independent predictor of subclinical atherosclerosis and coronary plaque burden, with its effects being mediated through PCSK9. These findings suggest that targeting PCSK9 could mitigate the inflammatory actions of HNP1-3, offering potential therapeutic insights for atherosclerosis prevention. Show less

Stress is thought to be an important contributing factor for eating disorders; however, neural substrates underlying the complex relationship between stress and appetite are not fully understood. Using in vivo recordings from awake behaving mice, we show that various acute stressors activate catecholaminergic nucleus tractus solitarius (NTS Show less

Norepinephrine (NE) is a well-known appetite regulator, and the nor/adrenergic system is targeted by several anti-obesity drugs. To better understand the circuitry underlying adrenergic appetite control, here we investigated the paraventricular hypothalamic nucleus (PVN), a key brain region that integrates energy signals and receives dense nor/adrenergic input, using a mouse model. We found that PVN NE level increases with signals of energy deficit and decreases with food access. This pattern is recapitulated by the innervating catecholaminergic axon terminals originating from NTS Show less