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CRP C-reactive protein; EPA eicosapentaenoic acid; IL intriguing interactive possibilities will be discussed: stress
interleukin; TNF tumor necrosis factor; LPS lipopolysaccha- influences food choices; stress enhances maladaptive meta-
ride; n-3 omega-3; n-6 omega-6; NF nuclear factor; bolic responses to unhealthy foods; diet can affect mood as
PUFA polyunsaturated fatty acid. well as proinflammatory responses to stressand more, as
illustrated in Figure 1. The evidence that vulnerabilities are
INTRODUCTION
not merely additive provides a window for considering new
T ogether, cardiovascular disease, cancer, and diabetes ac-
count for almost 70% of all deaths in the United States;
these diseases share inflammation as a common link (1,2).
multidisciplinary prospects.
J. K. KIECOLT-GLASER
supplementation, although there are also exceptions. Thus, provided by either variable alone. Although predicted cyto-
these dietary pathways have implications for both behavior kine levels were fairly consistent across n-6/n-3 ratios with
and inflammation. low depressive symptoms, higher n-6/n-3 ratios were associ-
Two key n-3 PUFAs, eicosapentaenoic acid (EPA) and ated with progressively elevated TNF- and IL-6 levels as
docosahexanoic acid, can substantially decrease lipopolysac- depressive symptoms increased. Accordingly, these studies
charide (LPS)-induced TNF- expression by blocking NF-B (26,28) suggested that diet can influence the magnitude of
activation (32,33). Moreover, EPA can also decrease LPS- inflammatory responses to stress and depression as well as
induced TNF- messenger ribonucleic acid in vitro, with the mood.
modulation of TNF- expression occurring at the transcrip-
tional level (32). Furthermore, oxidants and oxidized cell Stress Influences Food Choices
components can activate the NF-B pathway, promoting in- Both laboratory and epidemiological studies (42,43) sug-
flammation (4); the n-3 PUFAs also decrease oxidative stress gested that depression and stressful events motivate less
(34,35). Thus, n-3 PUFAs inhibition of NF-B transcriptional healthy food choices, although there may be greater risk
activity could influence expression of proinflammatory genes. related to being female, overweight, and scoring high on
High-fat meals can stimulate low-grade endotoxemia, dietary restraint. For example, stress and depression were
i.e., a rise in bacterial endotoxins, inflammatory antigens associated with less fresh fruit consumption as well as greater
that are typically found circulating at low concentrations in snack food intake among Chinese college students (44). Fe-
blood (36). High-fat meals can also induce NF-B activa- male college students (but not males) in Germany, Poland, and
tion in peripheral blood mononuclear cells (37). Impor- Bulgaria who reported more perceived stress ate more sweets
tantly, data from endotoxin challenges show that the n-3 and fast foods and fewer fruits and vegetables than those who
PUFAs can diminish these responses, simultaneously mod- were less stressed (45). Longitudinal data (46) from the Health
ulating changes in the hypothalamic-pituitary-adrenal and Professionals Study showed that men decreased their vegeta-
sympathetic-adrenal-medullary axes. ble intake after divorce or bereavement, and they increased
Bacterial endotoxin (LPS) administration heightens NF-B consumption after remarriage. Thus, in general, stress and
activation and produces acute behavioral, neuroendocrine, and depression promote less healthy food choices that can boost
inflammatory changes; the characteristic rise in negative inflammation. Stress compounds the problem by promoting
mood symptoms after an endotoxin challenge has been used as adverse metabolic responses to unhealthy meals.
a behavioral model of depression (38). Fish oil (which con-
tains EPA and docosahexanoic acid) alters these responses Stress Influences Metabolic Responses to Food
(39,40). For example, rises in plasma adrenocorticotropic hor- Within an hour of eating a meal high in saturated fat,
mone, norepinephrine, and TNF- were, respectively, four- circulating triglycerides rise and can remain elevated for 5
fold, seven-fold, and two-fold lower, after an intravenous fish hours to 8 hours (47). Postprandial lipemia (abnormally high
oil fat emulsion before LPS administration compared with lipids after a meal) is associated with Type II diabetes, met-
those randomized to no treatment; fish oil also blunted the rise abolic syndrome, obesity, and enhanced cardiovascular risk
in body temperature compared with controls (40). Subjects (47). Furthermore, when high-fat meals flood the body with
who received n-3 supplements for 3 weeks to 4 weeks before glucose and triglycerides, they provoke spikes in IL-6 and
an endotoxin challenge had lower norepinephrine, adrenocor- CRP, at the same time enhancing oxidative stress and sympa-
ticotropic hormone, plasma cortisol, and body temperature thetic hyperactivity; termed postprandial dysmetabolism, this
responses compared with the same subjects responses post cascade promotes endothelial dysfunction and, thus, athero-
placebo treatment; differences in TNF- and IL-6 were not genesis (48). Postprandial lipemia can represent either higher
significant in this small sample of 15 subjects (39). Although postmeal peaks or delays in clearance, either of which can
mood was not assessed in either of these studies, dietary n-3 promote the accumulation of atherogenic-triglyceride-rich
fatty acids attenuated LPS-induced depression-like behaviors remnant lipoproteins (49). Importantly, stress both enhances
in mice (41). post-meal peaks and delays clearance.
Paralleling and extending the endotoxin data, other evi- For example, one study showed that hourly mental stress
dence (26) suggested that the n-3 PUFAs may influence substantially augmented postprandial lipemia; the total trig-
immune responses to psychological stressors. For example, lycerol and very low-density-lipoprotein-triglycerol areas un-
medical students who /had lower serum n-3 or higher n-6/n-3 der the curve were 50% higher during stress than under
ratios before examinations demonstrated greater TNF- and control conditions (50). In an elegant study from Stoney and
interferon- production by LPS-stimulated peripheral blood colleagues (51), acute stress also slowed triglyceride clearance
leukocytes during examinations than those with higher n-3 or after an intravenously administered fat emulsion. Compared
lower ratios. with the nonstress session, clearance of an exogenous fat load
Furthermore, another study (28) with older adults sug- took 14% longer on average after a laboratory stressor.
gested that depressive symptoms and n-6/n-3 ratios worked Stress alters gastroduodenal motility, slows gastric empty-
together to enhance inflammation beyond the contribution ing, and perturbs intestinal transit and colonic motility (52).
J. K. KIECOLT-GLASER
Because the vagus nerve innervates tissues involved in the sponses to chemotherapy and the concomitant increases in
digestion, absorption, and metabolism of nutrients, including depressive symptoms and fatigue, as well as whether fasting
the stomach, pancreas, and liver, vagal activation directly and alters chemotherapy-induced cognitive changes (59).
profoundly influences metabolic responses to food (53). For A broader and deeper interface between the behavioral and
example, vagal activation is important in the regulation of nutritional camps is essential to building our knowledge
early and peak insulin responses that help to govern postpran- within each of the separate worlds. Stronger bridges between
dial glucose levels (53); in turn, the glucose response to meals the fields will also shed light on the forces promoting obesity-
helps to determine postprandial inflammation (48). Both de- related diseases. At a minimum, assessing diet more rigor-
pression and stress have well-documented negative effects on ously in behavioral studies and assessing behavior more
vagal activation as indexed by heart rate variability (52,54), routinely in dietary studies would provide important informa-
providing another pathway through which negative emotions tion on what might otherwise be seen as error variance. In
may influence postprandial inflammation. In short, the brain short, a better understanding of how stressors, negative emo-
and the gut have a vigorous, ongoing dialogue. tions, and unhealthy meals work together to enhance inflam-
mation will benefit behavioral and nutritional research, as well
Multidisciplinary Opportunities as the broader biomedical community.
Behavioral data are a relative rarity in the nutritional liter-
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