Legendre, Ariadne, and Ruth B. S. Harris. Exaggerated response to mild stress in rats fed high-fat diet. Am J Physiol Regul Integr Comp Physiol 291: R1288 -R1294, 2006. First published June 22, 2006 doi:10.1152/ajpregu.00234.2006.-It has been suggested that high-fat (HF) diet exaggerates the stress-induced release of glucocorticoids due to activation of the hypothalamic-pituitary-adrenal (HPA) axis. In an initial experiment, in which rats were fed HF diet for 4 days, we found that HF-fed controls stopped gaining weight, indicating that they were hyperresponsive to the mild stress of tail bleeding but responded the same as low-fat (LF)-fed rats to the more severe stress of restraint. A second experiment confirmed these results when rats fed a HF diet for 4 days showed an exaggerated corticosterone release in response to an intraperitoneal injection of saline and movement to a novel cage, compared with LF-fed rats. Experiment 3 tested the same parameters as experiment 2 but interchanged the diets. This allowed us to differentiate between the effects of the dietary fat and the novelty of the diet. Additionally, this experiment determined whether hyperresponsiveness to mild stress in HF-fed rats was sustained during a prolonged exposure to diet. The results confirmed that a HF diet, not novelty, exaggerated the endocrine stress response after 9 days on the diet but that the effect was no longer present after 23 days on the diet. The hyperresponsiveness of the HPA axis in HF-fed rats is similar to that observed in animals that have been exposed to a significant chronic or acute stress, suggesting that the HF diet may initially be perceived as a stressor.corticotropin-relasing factor; energy intake; hypothalamo-pituitary axis; weight regulation STRESS ACTIVATES DIFFERENT behavioral and physiological systems to allow an animal, or individual, to adapt to, or respond to, a change in environment or a socially stressful situation. The physiological response to stress is, in part, regulated by hormones released by the hypothalamic-pituitary-adrenal (HPA) axis (3,5,24). The CRF system is the primary initiator of neurochemical, behavioral, and endocrine response to stress (3). In regard to the HPA axis, stress-induced stimulation of the neuropeptide CRF in the hypothalamus, promotes release of ACTH from the anterior pituitary gland, which then stimulates the adrenal gland to release glucocorticoids, corticosterone for rodents, and cortisol for humans. These responses are apparent in a variety of rodent models of acute or intermittent stress, such as repeated restraint (12), immobilization (17), and social defeat (9). There is a negative feedback mechanism in place, so that free corticosterone acts on the pituitary and hypothalamus to down-regulate expression of ACTH and CRF, respectively. In addition to maintaining homeostasis in response to stress, CRF plays an important regulatory role in energy balance. Rodents exposed to stress have been shown to decrease food intake (26, 27), decrease weight gain (12, 15), and increase...

Chronic stress can have a deleterious effect on the re-productive axis that, for females, is manifested in an increased incidence of infertility. However, gonadal steroids may, in turn, affect a female's response to stress as measured by activity within the limbic-hypothalamic-pituitary-adrenal (LHPA) axis. What is not clear is whether a history of exposure to stress modifies the effect of gonadal steroids on LHPA responsivity. Rhesus monkeys present a unique opportunity to assess LHPA responsivity when housed socially in groups. Under these situations, monkeys exhibit a rich network of affiliation and have established social status hierarchies. Previous work indicates that socially subordinate macaque females are hypercortisolemic due to diminished gluco-corticoid negative feedback. The present study tested the hypothesis that estradiol (E2) would decrease gluco-corticoid negative feedback, assessed from a dexamethasone (DEX) suppression test, and increase the response to corticotropin releasing factor (CRF) and that these effects would be attenuated by co-treatment with P4. In addition, we also determined whether E2 and P4 would differentially affect LHPA responsiveness to pharmacological challenge in socially dominant compared with subordinate females. Endogenous gonadal hormone secretion in female rhesus monkeys (n = 7) was suppressed by continuous treatment with a sustained release formulation of the GnRH analog leuprolide acetate (Lupron Depot). The response to a combined DEX suppression-CRF stimulation test was assessed using a counterbalanced design during a placebo (control) treatment condition and during E2, P4, and E2 + P4 re-placement therapy. Females who were members of a large breeding group of 140 adults and juveniles of both sexes, were classified as dominant (n = 4) or subordinate (n = 3) based on the relative social dominance positions within the group. Plasma levels of cortisol were significantly higher during E2 replacement compared to the other treatment conditions following DEX suppression and stimulation with CRF.

The importance of leptin in regulating sexual maturation is supported by data showing that deletions of the leptin gene or alterations in the leptin receptor result in infertility. However, attempts to define a role for leptin in normal puberty have produced equivocal results, leading to the conclusion that, if leptin is involved in puberty, its role is permissive and not obligatory. To better define the importance of leptin in primate puberty, the present study tested the hypothesis that a premature elevation in nocturnal leptin concentrations would accelerate indices of puberty, including nocturnal LH secretion in female rhesus monkeys (Macaca mulatta). Juvenile, gonadally intact females were treated daily with leptin (n = 6; 30 micro g/kg, sc at 1700 h) from 12-30 months of age and were compared with age-matched control females (n = 13). Chronic elevation in peripheral concentrations of leptin increased serum levels of both daytime and nighttime bioactive LH at a significantly younger age compared with control females. The earlier rise in LH in leptin-treated females was associated with an earlier increase in serum estradiol and occurrence of menarche. Despite this effect of leptin, nocturnal serum LH was significantly higher at each age assessed in non-leptin-treated ovariectomized controls (n = 6). In addition, leptin increased skeletal lengths and maturity that were associated with significantly higher serum levels of nocturnal GH and daytime IGF-I. Although body weights were not consistently affected by treatment, body mass index, as an index of body fat, was consistently lower in leptin-treated females. Taken together, these data indicate that the chronic elevation in serum leptin concentrations advances the nocturnal increase in serum LH as well as other parameters of female puberty. Furthermore, the observation that nocturnal LH was higher in age-matched, agonadal females compared with the leptin-treated females suggests that the nongonadal drive to LH secretion is operative in female macaques as early as 14 months of age, suggesting that the effect of leptin on puberty in female primates may involve a diminution in gonadal negative feedback suppression of LH secretion. Such a role would suggest that leptin is permissive yet critical for advancing female puberty.

We previously reported an exaggerated endocrine and weight loss response to stress in rats fed a high-fat (HF) diet for 5 days. Others report blunted stress-induced anxiety in rats made obese on a HF diet. Experiments described here tested whether sensitivity to stress-related peptides was changed in obese and nonobese HF-fed rats. Third ventricle infusion of corticotropin-releasing factor (CRF) in rats made obese on HF diet (40% kcal fat) produced an exaggerated hypophagia, which is thought to be mediated by CRF(2) receptors. Obese rats responded to a lower dose of CRF for a longer time than rats fed a low-fat (LF) diet (12% kcal fat). CRF-induced release of corticosterone, which is thought to be mediated by CRF(1) receptors, was not exaggerated in obese HF-fed rats. In contrast, rats fed HF diet for 5 days showed the same food intake and corticosterone response to CRF as LF-fed rats. CRF mRNA expression in the paraventricular nucleus of the hypothalamus was stimulated by mild stress (ip saline injection and placement in a novel cage) in LF-fed rats but not in rats fed HF diet for 5 days because of a nonsignificant increase in expression in nonstressed HF-fed rats. In addition, nonstressed levels of urocortin (UCN) I mRNA expression in the Edinger-Westphal nucleus were significantly inhibited in HF-fed rats. These data suggest that rats that have become obese on a HF diet show a change in responsiveness to stress peptides, whereas the increased stress response in nonobese HF-fed rats may be associated with changes in basal CRF and UCN I mRNA expression.