Lydia Kuo

Neuropeptide Y acts directly in the periphery on fat tissue and mediates stress-induced obesity and metabolic syndrome.

The relationship between stress and obesity remains elusive. In response to stress, some people lose weight, whereas others gain. Here we report that stress exaggerates diet-induced obesity through a peripheral mechanism in the abdominal white adipose tissue that is mediated by neuropeptide Y (NPY). Stressors such as exposure to cold or aggression lead to the release of NPY from sympathetic nerves, which in turn upregulates NPY and its Y2 receptors (NPY2R) in a glucocorticoid-dependent manner in the abdominal fat. This positive feedback response by NPY leads to the growth of abdominal fat. Release of NPY and activation of NPY2R stimulates fat angiogenesis, macrophage infiltration, and the proliferation and differentiation of new adipocytes, resulting in abdominal obesity and a metabolic syndrome-like condition. NPY, like stress, stimulates mouse and human fat growth, whereas pharmacological inhibition or fat-targeted knockdown of NPY2R is anti-angiogenic and anti-adipogenic, while reducing abdominal obesity and metabolic abnormalities. Thus, manipulations of NPY2R activity within fat tissue offer new ways to remodel fat and treat obesity and metabolic syndrome.

Chronic Stress, Combined with a High‐Fat/High‐Sugar Diet, Shifts Sympathetic Signaling toward Neuropeptide Y and Leads to Obesity and the Metabolic Syndrome

In response to stress, some people lose while others gain weight. This is believed to be due to either increased β‐adrenergic activation, the bodys main fat‐burning mechanism, or increased intake of sugar‐ and fat‐rich “comfort foods.” A high‐fat, high‐sugar (HFS) diet alone, however, cannot account for the epidemic of obesity, and chronic stress alone tends to lower adiposity in mice. Here we discuss how chronic stress, when combined with an HFS diet, leads to abdominal obesity by releasing a sympathetic neurotransmitter, neuropeptide Y (NPY), directly into the adipose tissue. In vitro, when “stressed” with dexamethasone, sympathetic neurons shift toward expressing more NPY, which stimulates endothelial cell (angiogenesis) and preadipocyte proliferation, differentiation, and lipid‐filling (adipogenesis) by activating the same NPY‐Y2 receptors (Y2Rs). In vivo, chronic stress, consisting of cold water or aggression in HFS‐fed mice, stimulates the release of NPY and the expression of Y2Rs in visceral fat, increasing its growth by 50% in 2 weeks. After 3 months, this results in metabolic syndrome‐like symptoms with abdominal obesity, inflammation, hyperlipidemia, hyperinsulinemia, glucose intolerance, hepatic steatosis, and hypertension. Remarkably, local intra‐fat Y2R inhibition pharmacologically or via adenoviral Y2R knock‐down reverses or prevents fat accumulation and metabolic complications. These studies demonstrated for the first time that chronic stress, via the NPY‐Y2R pathway, amplifies and accelerates diet‐induced obesity and the metabolic syndrome. Our findings also suggest the use of local administration of Y2R antagonists for treatment of obesity and NPY‐Y2 agonists for fat augmentation in other clinical applications.

Differential Effects of Neuropeptide Y on the Growth and Vascularization of Neural Crest–Derived Tumors

Neuropeptide Y (NPY) is a sympathetic neurotransmitter recently found to be potently angiogenic and growth promoting for endothelial, vascular smooth muscle and neuronal cells. NPY and its cognate receptors, Y1, Y2 and Y5, are expressed in neural crest-derived tumors; however, their role in regulation of growth is unknown. The effect of NPY on the growth and vascularization of neuroendocrine tumors was tested using three types of cells: neuroblastoma, pheochromocytoma, and Ewings sarcoma family of tumors (ESFT). The tumors varied in expression of NPY receptors, which was linked to differential functions of the peptide. NPY stimulated proliferation of neuroblastoma cells via Y2/Y5Rs and inhibited ESFT cell growth by Y1/Y5-mediated apoptosis. In both tumor types, NPY receptor antagonists altered basal growth levels, indicating a regulatory role of autocrine NPY. In addition, the peptide released from the tumor cells stimulated endothelial cell proliferation, which suggests its paracrine angiogenic effects. In nude mice xenografts, exogenous NPY stimulated growth of neuroblastoma tumors, whereas it increased apoptosis and reduced growth of ESFT. However, in both tumors, NPY treatment led to an increase in tumor vascularization. Taken together, this is the first report of NPY being a growth-regulatory factor for neuroendocrine tumors, acting both by autocrine activation of tumor cell proliferation or apoptosis and by angiogenesis. NPY and its receptors may become targets for novel approaches in the treatment of these diseases, directed against both tumor cell proliferation and angiogenesis.

Stress, NPY and vascular remodeling: Implications for stress-related diseases

Neuropeptide Y (NPY) has long been known to be involved in stress, centrally as an anxiolytic neuromodulator, and peripherally as a sympathetic nerve- and in some species, platelet-derived vasoconstrictor. The peptide is also a vascular mitogen, via Y1/Y5, and is angiogenic via Y2/Y5 receptors. Arterial injury activates platelet NPY and vascular Y1 receptors, inducing medial hypertrophy and neointima formation. Exogenous NPY, dipeptidyl peptidase IV (DPPIV, forming an Y2/Y5-selective agonist) and chronic stress augment these effects and occlude vessels with atherosclerotic-like lesions, containing thrombus and lipid-laden macrophages. Y1 antagonist blocks stress-induced vasoconstriction and post-angioplasty occlusions, and hence may be therapeutic in angina and atherosclerosis/restenosis. Conversely, tissue ischemia activates neuronal and platelet-derived NPY, Y2/Y5 and DPPIV, which stimulate angiogenesis/arteriogenesis. NPY-Y2-DPPIV agonists may be beneficial for ischemic revascularization and wound healing, whereas antagonists may be therapeutic in retinopathy, tumors, and obesity. Since stress is an underestimated risk factor in many of these conditions, NPY-based drugs may offer new treatment possibilities.

Neuropeptide Y and its Y2 receptor: potential targets in neuroblastoma therapy

Neuroblastomas are pediatric tumors that develop from sympathetic precursors and express neuronal proteins, such as neuropeptide Y (NPY). NPY is a sympathetic neurotransmitter acting via multiple receptors (Y1–Y5R). Both NPY and Y2Rs are commonly expressed in neuroblastoma cell lines and tissues. The peptide secreted from neuroblastomas stimulates tumor cell proliferation and angiogenesis. As both processes are Y2R-mediated, the aim of this study was to assess Y2R as a potential therapeutic target for neuroblastoma. In vitro, Y2R antagonist (BIIE0246) prevented activation of p44/42 mitogen-activated protein kinase (MAPK) induced by endogenous NPY, which resulted in decreased proliferation and induction of Bim-mediated apoptosis. Similar growth-inhibitory effects were achieved with NPY small interfering RNA (siRNA) and Y2R siRNA. In vivo, Y2R antagonist significantly inhibited growth of SK-N-BE(2) and SK-N-AS xenografts, which was associated with decreased activation of p44/42 MAPK, as well as reduced proliferation (Ki67) and increased apoptosis (TdT-mediated dUTP nick end labeling; TUNEL). The Y2R antagonist also exerted an antiangiogenic effect. In vitro, it reduced the proliferation of endothelial cells induced by neuroblastoma-conditioned media. Consequently, the Y2R antagonist-treated xenografts had decreased vascularization and a high degree of focal fibrosis. In human neuroblastoma tissues, the expression of Y2R was observed in both tumor and endothelial cells, while NPY was predominantly expressed in neuroblastoma cells. In summary, Y2R is a promising new target for neuroblastoma therapy affecting both cancer cells and tumor vasculature.

Neuropeptide Y is a mediator of chronic vascular and metabolic maladaptations to stress and hypernutrition

Neuropeptide Y (NPY) is a central neuromodulator and peripheral sympathetic neurotransmitter that also has important regulatory roles in cardiovascular, neuroendocrine, immune and metabolic functions during stress. Focusing on the peripheral actions of the peptide in rodent models, we summarize recent studies from our laboratory demonstrating that stress-induced release of NPY mediates accelerated atherosclerosis/restenosis, obesity and metabolic-like syndrome, particularly when combined with a high fat, high sugar diet. In this review, we propose mechanisms of NPYs actions, its receptors and cellular substrates that increase the risk for cardiovascular and metabolic diseases when chronic stress is associated with pre-existing vascular injury and/or states of hypernutrition.

The role of the neuropeptide Y2 receptor in liporemodeling: neuropeptide Y-mediated adipogenesis and adipose graft maintenance.

Background: Neuropeptide Y is a signaling molecule that was recently found to stimulate adipose tissue growth in vitro by means of a peripherally acting mechanism involving the neuropeptide Y2 receptor found on adipocytes and endothelial cells. This study aims to evaluate the translational applications of a neuropeptide Y2 receptor agonist for autologous fat grafting in plastic surgery. Methods: Murine and primate animal models were used to investigate the proliferative effects of neuropeptide Y on adipose tissue. The effect of applying neuropeptide Y to subcutaneous tissues in mice and monkeys was assessed by magnetic resonance imaging, histology, and immunohistochemistry. The effect of neuropeptide Y on human fat xenograft survival and vascularity in athymic mice was measured by ultrasonography and immunohistochemistry. Six animals per group were used in murine experiments, and two animals were used in the pilot primate study. Results: Neuropeptide Y stimulated growth of adipose tissues when applied subcutaneously in mice and monkeys, and increased human fat xenograft survival and vascularity in athymic mice at 3 months. Conclusions: These data provide in vivo evidence for a critical role for neuropeptide Y/neuropeptide Y2 receptor interactions in adipogenesis, and suggest neuropeptide Y2 receptor as a potential target for agonist compounds that can be used to enhance fat graft survival or stimulate de novo adipogenesis.

NPY as a mediator of neurogenic angiogenesis and revascularization of ischemic tissues

NPY is a sympathetic neurotransmitter and a mediator of neurogenic angiogenesis in many tissues, such as skeletal muscles, tumors, retina, skin, adipose tissue and possibly the nervous system itself. It stimulates endothelial cell adhesion, migration, proliferation and differentiation leading to the formation of capillaries by activating the Y2 and Y5 receptors. NPY also stimulates vascular smooth muscle cell proliferation via the Y1 and Y5 receptors, and thus is able to form collateral arteries. Ischemia upregulates the NPY-Y2 receptor system and the peptide improves revascularization and ischemic skeletal muscle function. We propose that NPY is a mediator of a sympathetic trophic cycle, acting to adjust vessel development to that of nerves and vice versa, and thus promoting tissue growth. As a neurotransmitter, NPY is positioned at the beginning of the cascade that activates downstream mediators leading to angiogenesis, arteriogenesis and neurogenesis in a tissue-specific manner. These potent and multi-faceted activities of NPY make the peptide’s Y2/Y5 receptor agonists valuable new targets for revascularization therapy, and its Y2/Y5 antagonists potential drugs to inhibit excessive growth of organs such as adipose tissue or tumors.