cp-154526 and Body-Weight

Psychosocial factors, particularly social stress, may compromise reproduction. However, some individuals may be more susceptible to socially induced infertility. The present study used group-housed, adult, ovariectomized rhesus monkeys to test the hypothesis that exposure to psychosocial stress, imposed by social subordination, would enhance estradiol (E2)-negative feedback inhibition of LH. Because polymorphisms in the gene encoding the serotonin transporter (SLC6A4) may contribute to individual differences in response to adverse environments, we determined whether subordinate females with the short-promoter-length allele (s-variant) would show greater suppression of LH. Subordinate females, particularly those with the s-variant SLC6A4 genotype, received significantly higher rates of noncontact aggression from more dominant cage mates and had consistently lower body weights. Serum LH was not influenced by social status in the absence of E2. In contrast, subordinate females were hypersensitive to E2-negative feedback inhibition of LH. Furthermore, serum LH in subordinate females with s-variant SLC6A4 genotype was maximally suppressed by Day 4 of treatment, whereas nadir concentrations were not reached until later in treatment in other females. Finally, pharmacological elevation of serum cortisol potentiated E2-negative feedback inhibition in all females. The current data suggest that infertility induced by psychosocial stressors may be mediated by hypersensitivity to E2-negative feedback and that polymorphisms in the SLC6A4 gene may contribute to differences in reproductive compromise in response to chronic stress.

Topics: Analysis of Variance; Animals; Body Weight; Dominance-Subordination; Estradiol; Female; Hydrocortisone; Hypothalamo-Hypophyseal System; Individuality; Luteinizing Hormone; Macaca mulatta; Pituitary-Adrenal System; Polymorphism, Genetic; Pyrimidines; Pyrroles; Radioimmunoassay; Receptors, Corticotropin-Releasing Hormone; Serotonin Plasma Membrane Transport Proteins; Social Environment; Stress, Psychological

To determine the influence of continuous hypoxia on body weight, food intake, hepatic glycogen, circulatory glucose, insulin, glucagon, leptin, and corticosterone, and the involvement of the corticotropin-releasing factor receptor type 1 (CRFR1) in modulation of these hormones, rats were exposed to a simulated altitude of 5 km (approximately 10.8% O2) in a hypobaric chamber for 1, 2, 5, 10, and 15 d. Potential involvement of CRFR1 was assessed through five daily sc injections of a CRFR1 antagonist (CP-154,526) prior to hypoxia. Results showed that the levels of body weight, food intake, blood glucose, and plasma insulin were significantly reduced; the content of hepatic glycogen initially and transiently declined, whereas the early plasma glucagon and leptin remarkably increased; plasma corticosterone was markedly increased throughout the hypoxic exposure of 1-15 d. Compared with hypoxia alone, CRFR1 antagonist pretreatment in the hypoxic groups prevented the rise in corticosterone, whereas the levels of body weight and food intake were unchanged. At the same time, the reduction in blood glucose was greater and the pancreatic glucose was increased, plasma insulin reverted toward control, and plasma glucagon decreased. In summary, prolonged hypoxia reduced body weight, food intake, blood glucose, and plasma insulin but transiently enhanced plasma glucagon and leptin. In conclusion, CRFR1 is potentially involved in the plasma insulin reduction and transient glucagon increase in hypoxic rats.

Topics: Altitude; Animals; Blood Glucose; Body Weight; Corticosterone; Eating; Glucagon; Hypoxia; Insulin; Leptin; Liver Glycogen; Male; Pyrimidines; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, Corticotropin-Releasing Hormone