Maternal Stress – Neuropeptide Y System – Vulnerability to Obesity
A recent report in the FASEB Journal indicates that Neuropeptide Y (NPY) system is a potential mediator of programming for the offspring’s vulnerability to obesity and metabolic syndrome induced by maternal low-protein diet (LPD).
According to CDC more than one-third of U.S. adults (35.7%) are obese. As stated by Ogden C. et al., 17.1% of U.S. children are now obese, and overall, up to 2/3 of children and adolescents in the United States are overweight or obese (JAMA, 2006, 295, 1549). According to Wikipedia and Forbes, United Kingdom has the most overweight population in Europe, with 22% of Britons now obese.
Obesity is a multifactorial condition. Among the ‘environmental’ factors, psychological stress may play an important role, even though this factor is often overlooked among the long list of causes related to excess weight gain. Traditionally, stress is linked to obesity through hypothalamic effects on food intake or peripherally, through catecholamine-mediated beta-adrenergic effects, or glucocorticoid and parasympathetic activity. The role of these factors in chronic stress, however, remains uncertain.
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. Chronic stress, however, when combined with an HFS diet, leads to abdominal obesity by releasing a sympathetic neurotransmitter, neuropeptide Y (NPY), directly into the adipose tissue.
Of note, the adrenergic co-transmitter NPY is released primarily in conditions of prolonged activation of the sympathetic nerves, observed during chronic stress, and recent research has implicated NPY in the pathogenesis of obesity. NPY is a major component of the stress response, and often synergizes with the actions of the major stress hormones such as glucocorticoids and catecholamines.
A recent study indicates that chronic stress in mice, combined with high-fat diet (HFD), results in up-regulation of NPY and NPY2 (Y2R) receptor expression in visceral adipose tissue (VAT), where the activation of the VAT NPY-Y2R systems leads to abdominal obesity and metabolic-like syndrome (Kuo, L. et al., 2007, Nat. Med. 13, 803).
Interestingly, in humans and animals, maternal stress, psychosocially or metabolically [e.g., low-protein diet (LPD); 8% protein], increases the risk of obesity and diabetes in the progeny. Stress-induced programming can be mimicked by maternal exposure to an excess of glucocorticoids in rodents and humans and has been linked to epigenetic regulation of the hypothalamic-pituitary-adrenal (HPA) axis. Of note, centrally, NPY is anxiolytic and also potently orexigenic. Thus, increased activity of NPY and its receptors, Y1R, Y2R, and Y5R, has been found to be involved in many forms of experimental obesity.
In the FASEB study, Ruijun Han and colleagues from the Department of Integrative Biology and Physiology, Stress Physiology Center, University of Minnesota, Minneapolis, Minnesota, investigated whether the NPY system also plays a role in the programming of obesity induced by maternal low-protein diet (LPD).
The maternal LPD has been used extensively in rats to demonstrate the importance of the early environment in determining susceptibility to future development of obesity and diabetes, particularly in male offspring. The authors used two paradigms: pregnancy and lactation stress (PLS), with maternal LPD during pregnancy and lactation; or pregnancy stress (PS), with maternal LPD only during pregnancy, and cross-fostering of offspring after birth to control mothers fed a normal-protein diet (NPD).
In this study, female offspring of mice fed LPD during pregnancy and lactation had lower birth weight but grew faster on HFD and developed abdominal adiposity and glucose intolerance compared to control females. This impaired metabolic phenotype was associated with elevated circulating NPY levels and up-regulation of NPY-Y2R adipogenic pathway in the visceral fat. In contrast, male offspring from LPD mothers also had lower birth weight but accumulated less fat and had improved glucose tolerance and lower systemic levels of NPY and intrafat Y2R expression compared to control males. Interestingly, prenatal LPD offspring cross-fostered to control lactating mothers had completely inverse metabolic and NPY phenotypes.
The authors propose that the peripheral NPY system is a mediator and a marker for adult obesity and metabolic dysfunction induced by maternal stress. They conclude that maternal LPD may induce gender-specific regulation on the peripheral NPY system, specifically NPY in the PRP and Y2R in the visceral fat, and therefore program for future development of abdominal obesity and metabolic syndrome.