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 beta-adrenergic activation, the body's 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.

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.