Agouti yellow mutation increases adrenal response to ACTH in mice.
OBJECTIVE
Agouti protein (AP) and agouti-related protein with a similar sequence and action are endogenous antagonists of melanocortin receptors, implicated in the control of the hypothalamo-pituitary-adrenal (HPA) axis. Dominant mutation of the agouti gene (agouti yellow (A(y))) in heterozygous A(y)/a mice leads to ectopic overexpression of AP and produces an obese phenotype. The existing data on the HPA function in A(y)/a-mice are equivocal; therefore, the present study aimed to assess HPA function in 3-month-old male C57Bl/6J mice of two agouti genotypes: A(y)/a (ectopic AP overexpression) and a/a (absence of AP).


METHODS
In order to evaluate the HPA function, activating (15-min restriction, ACTH-induced corticosterone production in vitro) and inhibiting (i.p. injection of dexamethasone, 0.02 microg/g body weight) stimuli were employed. To estimate the effect of obesity on some HPA functions, A(y)/a males were subdivided into obese and non-obese groups.


RESULTS
Basal plasma concentrations of ACTH and corticosterone; basal corticosterone production in vitro; and feedback inhibition of resting corticosterone levels by dexamethasone were similar in A(y)/a- and a/a-mice. Restraint-induced plasma corticosterone was greater in obese and non-obese A(y)/a-mice than in a/a-mice, whereas restraint-induced plasma ACTH levels were similar. Adrenal cell responses to ACTH (10(-13)-10(-10) M) were higher in obese and non-obese A(y)/a-mice than in a/a-mice. Dexamethasone, injected 3 h prior to stress, inhibited stress-induced corticosterone levels by a significantly greater amount in A(y)/a-mice than in a/a-mice.


CONCLUSIONS
AP may have both stimulating and inhibiting influences on the HPA axis. AP overproduction increased the response of the HPA to short-restraint stress due to increased adrenal responsiveness to ACTH; this result was not effected by obesity development.
Bazhan
Nadezhda M
NM
Institute of Cytology and Genetics, Russian Academy of Sciences, Pr. Lavrentjeva 10, Novosibirsk 630090, Russia. bazhan@bionet.nsc.ru
Shevchenko
Antonina Y
AY
Karkaeva
Nelli R
NR
Yakovleva
Tatyana V
TV
Makarova
Elena N
EN
D000311:Adrenal Glands / Q000187:drug effects / Q000502:physiology*; D000324:Adrenocorticotropic Hormone / Q000097:blood*; D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; D000818:Animals; D003345:Corticosterone / Q000097:blood; D003907:Dexamethasone / Q000494:pharmacology; D005838:Genotype; D005938:Glucocorticoids / Q000494:pharmacology; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009154:Mutation; D009765:Obesity / Q000503:physiopathology; D010913:Pituitary-Adrenal System / Q000187:drug effects / Q000502:physiology; D012149:Restraint, Physical; D013312:Stress, Physiological / Q000503:physiopathology
D054366:Agouti Signaling Protein; D054369:Agouti-Related Protein; C515199:Agrp protein, mouse; D005938:Glucocorticoids; D036341:Intercellular Signaling Peptides and Proteins; C515183:a protein, mouse; D003907:Dexamethasone; D000324:Adrenocorticotropic Hormone; D003345:Corticosterone