Dietary n-3:n-6 fatty acid ratios differentially influence hormonal signature in a rodent model of metabolic syndrome relative to healthy controls.

Dietary ratios of omega-3 (n-3) to omega-6 (n-6) polyunsaturated fatty acids (PUFAs) have been implicated in controlling markers of the metabolic syndrome, including insulin sensitivity, inflammation, lipid profiles and adiposity. However, the role of dietary PUFAs in regulating energy systems in healthy relative to metabolic diseased backgrounds has not been systematically addressed. We used dietary manipulation of n-3 to n-6 PUFA ratios in an animal model of metabolic syndrome and a related healthy line to assay feeding behavior and endocrine markers of feeding drive and energy regulation. Two related lines of rodents with a healthy and a metabolic syndrome phenotype were fed one of two isocaloric diets, comprised of either a 1:1 or a 1:30 n-3 to n-6 ratio, for 30 days. Food intake and weight gain were monitored; and leptin, ghrelin, adiponectin and a suite of hypothalamic neuropeptides involved in energy regulation were assayed following the dietary manipulation period. There was no difference in caloric intake or weight gain between diet groups, however there was a significant interaction between diet and phenotypic line on central and peripheral markers of energy homeostasis. Thus serum levels of leptin, acylated-ghrelin and adiponectin, and mRNA levels of the anorexigenic hypothalamic neuropeptide, cocaine-amphetamine related transcript (CART), showed differential, dietary responses with HCR rats showing an increase in anorexigenic signals in response to unbalanced n-3:6 ratios, while LCR did not. These data are the first to demonstrate that a rodent line with a metabolic syndrome-like phenotype responds differentially to dietary manipulation of n-3 and n-6 fatty acids relative to a related healthy line with regard to endocrine markers of energy homeostasis. The dietary n-3:n-6 ratios used in this experiment represent extreme points of natural human diets, however the data suggest that optimal recommendations regarding omega-3 and omega-6 intake may have differing effects in healthy subjects relative to metabolic syndrome patients. Further research is necessary to establish these responses in human populations.

Overexpressing the glucocorticoid receptor in forebrain causes an aging-like neuroendocrine phenotype and mild cognitive dysfunction.

Repeated stress enhances vulnerability to neural dysfunction that is cumulative over the course of the lifespan. This dysfunction contributes to cognitive deficits observed during aging. In addition, aging is associated with dysregulation of the limbic-hypothalamic-pituitary-adrenal (LHPA) axis, leading to a delayed termination of the stress response. This delay, in turn, increases exposure to glucocorticoids and exacerbates the likelihood of neural damage. Here we asked whether similar effects could emerge at an early age as a result of genetic variations in the level or function of the brain glucocorticoid receptor (GR). We investigated the effect of forebrain-specific overexpression of GR on LHPA axis activity. Transgenic mice with GR overexpression in forebrain (GRov) display normal basal circulating adrenocorticotropic hormone and corticosterone levels. However, young GRov mice exhibit a number of LHPA alterations, including a blunted initial response to acute restraint stress followed by a delayed turn-off of the stress response. This deficit in negative feedback is paradoxical in the face of elevated GR levels, resembles the stress response in aged animals, and continues to worsen as GRov mice age. The neuroendocrine dysregulation in young GRov mice is coupled with a mild cognitive deficit, also consistent with the accelerated aging hypothesis. The molecular basis of this phenotype was examined using microarray analysis of the hippocampus, which revealed a broad downregulation of glutamate receptor signaling in GRov mice. Thus, even in the absence of chronic stress, elevation of GR gene expression can lead to an increased allostatic load and result in an "aging-like" phenotype in young animals.

Gonadal hormones masculinize and defeminize reproductive behaviors during puberty in the male Syrian hamster.

Three experiments were conducted to test whether testicular hormones secreted during puberty masculinize and defeminize the expression of adult reproductive behavior. Experiment 1 tested the hypothesis that gonadal hormones during puberty masculinize behavioral responses to testosterone (T) in adulthood. Male hamsters were castrated either before puberty (noTduringP) or after puberty (TduringP). All males were implanted with a 2.5-mg T pellet 6 weeks following castration and tested once for masculine reproductive behavior 7 days after the onset of T replacement. TduringP males displayed significantly more mounts, intromissions, and ejaculations than noTduringP males. Experiment 2 tested the hypothesis that gonadal hormones during puberty defeminize behavioral responses to estrogen (EB) and progesterone (P). Eight weeks following castration, noTduringP and TduringP males were primed with EB and P and tested for lordosis behavior with a stud male. Behavioral responses of males were compared to that of ovariectomized (OVX) and hormone primed females. NoTduringP males and OVX females displayed significantly shorter lordosis latencies than TduringP males. Experiment 3 investigated whether prolonged T treatment or sexual experience could reverse the deficits in masculine behavior caused by the absence of T during puberty. Extending the T treatment from 7 to 17 days did not ameliorate the deficits in masculine behavior caused by absence of T during puberty. Similarly, when the level of sexual experience was increased from one to three tests, the deficits in masculine behavior persisted. These studies demonstrate that gonadal hormones during puberty further masculinize and defeminize neural circuits and behavioral responsiveness to steroid hormones in adulthood.