Neuropeptide Y (NPY) is a 36-amino acid peptide that is widely distributed in both the central and peripheral nervous systems. It plays a critical role in regulating energy balance, appetite, and metabolism. NPY is known for its potent orexigenic (appetite-stimulating) effects and its ability to reduce energy expenditure. The primary neurons that release NPY are located in the arcuate nucleus of the hypothalamus, where they project to the paraventricular nucleus. Once released, NPY binds to Y1 and Y5 receptors in this region, triggering feeding behavior and influencing metabolic processes.
In the periphery, NPY can modulate sympathetic and parasympathetic activity, which further affects energy regulation. Studies have shown that inhibiting NPY signaling reduces food intake, while fasting in non-obese mice leads to increased NPY levels in the hypothalamus. Additionally, NPY-expressing neurons in the arcuate nucleus co-localize with leptin receptors (OB-R), and leptin suppresses NPY synthesis and secretion, thereby reducing appetite and body fat accumulation. In ob/ob mice, which lack functional leptin, NPY levels must remain elevated to maintain metabolic function. Conversely, reduced NPY production leads to decreased food intake and weight loss, highlighting its essential role in weight regulation.
NPY belongs to the pancreatic polypeptide family and is one of the most abundant neuropeptides in the brain. Its physiological functions extend beyond appetite control. In the central nervous system, NPY has anti-anxiety and anti-epileptic properties, and it can inhibit reproductive functions, muscle excitability, and sympathetic activity, resulting in lower blood pressure, heart rate, and metabolic rate. However, in the periphery, NPY acts as a stimulator, enhancing stress responses through interactions with glucocorticoids and catecholamines. It also contributes to vascular remodeling, lipid dysregulation, and adipokine release.
The biological effects of NPY are mediated through its receptors, particularly Y1, Y2, Y5, and others. NPY undergoes enzymatic modification by dipeptidyl peptidase IV (DPPIV), converting NPY1-36 into NPY3-36, which has a higher affinity for Y2 and Y5 receptors. This modification enhances its biological activity and plays a role in immune responses, cell proliferation, and vascular remodeling.
NPY is involved in the formation of atherosclerotic plaques, especially through activation of Y1 and Y5 receptors, which promote smooth muscle cell proliferation and endothelial dysfunction. The Y2 receptor also contributes to plaque progression by synergizing with Y5 and stimulating endothelial cell migration and capillary formation. Additionally, NPY inhibits norepinephrine release from presynaptic terminals, which may contribute to long-term vasoconstriction and vascular remodeling under chronic stress conditions.
Stress-induced increases in plasma NPY levels have been observed in both animal models and humans. For example, cold stress in rats leads to elevated NPY, increased arterial pressure, and reduced mesenteric blood flow. These effects are partially blocked by Y1 receptor antagonists, indicating the receptor’s role in mediating vasoconstriction. Similarly, NPY causes coronary artery vasoconstriction in humans, mimicking the effects of psychological stress on cardiac blood flow.
Gender differences in NPY response have also been noted, with males generally showing greater NPY elevation and vascular reactivity compared to females. This may be related to the influence of sex hormones on NPY gene expression.
Beyond vascular effects, NPY promotes angiogenesis through Y2 receptor activation, aiding in the recovery of ischemic tissues. It stimulates endothelial cell proliferation, migration, and lumen formation, processes that are dependent on eNOS activity. NPY also induces the expression of growth factors like VEGF and bFGF, contributing to both physiological and pathological angiogenesis.
In addition to its role in cardiovascular health, NPY is implicated in mental health. Research suggests that low levels of NPY in the brain are associated with increased pessimism and depression. Functional MRI studies show that individuals with lower NPY exhibit heightened prefrontal cortex activity in response to negative stimuli, suggesting a link between NPY deficiency and emotional dysregulation.
Overall, NPY is a multifaceted molecule with significant implications in metabolism, stress response, cardiovascular disease, and mental health. Targeting NPY signaling pathways presents potential therapeutic opportunities for treating obesity, hypertension, depression, and vascular disorders.
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