Role of glucocorticoids in mediating effects of fasting and diabetes on hypothalamic gene expression.
BACKGROUND
Fasting and diabetes are characterized by elevated glucocorticoids and reduced insulin, leptin, elevated hypothalamic AGRP and NPY mRNA, and reduced hypothalamic POMC mRNA. Although leptin replacement can reverse changes in hypothalamic gene expression associated with fasting and diabetes, leptin also normalizes corticosterone; therefore the extent to which the elevated corticosterone contributes to the regulation of hypothalamic gene expression in fasting and diabetes remains unclear. To address if elevated corticosterone is necessary for hypothalamic responses to fasting and diabetes, we assessed the effects of adrenalectomy on hypothalamic gene expression in 48-hour-fasted or diabetic mice. To assess if elevated corticosterone is sufficient for the hypothalamic responses to fasting and diabetes, we assessed the effect of corticosterone pellets implanted for 48 hours on hypothalamic gene expression.


RESULTS
Fasting and streptozotocin-induced diabetes elevated plasma glucocorticoid levels and reduced serum insulin and leptin levels. Adrenalectomy prevented the rise in plasma glucocorticoids associated with fasting and diabetes, but not the associated reductions in insulin or leptin. Adrenalectomy blocked the effects of fasting and diabetes on hypothalamic AGRP, NPY, and POMC expression. Conversely, corticosterone implants induced both AGRP and POMC mRNA (with a non-significant trend toward induction of NPY mRNA), accompanied by elevated insulin and leptin (with no change in food intake or body weight).


CONCLUSIONS
These data suggest that elevated plasma corticosterone mediate some effects of fasting and diabetes on hypothalamic gene expression. Specifically, elevated plasma corticosterone is necessary for the induction of NPY mRNA with fasting and diabetes; since corticosterone implants only produced a non-significant trend in NPY mRNA, it remains uncertain if a rise in corticosterone may be sufficient to induce NPY mRNA. A rise in corticosterone is necessary to reduce hypothalamic POMC mRNA with fasting and diabetes, but not sufficient for the reduction of hypothalamic POMC mRNA. Finally, elevated plasma corticosterone is both necessary and sufficient for the induction of hypothalamic AGRP mRNA with fasting and diabetes.
Makimura
Hideo
H
Fishberg Center for Neurobiology, Neurobiology of Aging Laboratories, Mount Sinai School of Medicine, One Gustave L, Levy Place, New York, New York 10029, USA. Hideo.Makimura@mssm.edu
Mizuno
Tooru M
TM
Isoda
Fumiko
F
Beasley
Joe
J
Silverstein
Jeffrey H
JH
Mobbs
Charles V
CV
D000313:Adrenal Medulla / Q000502:physiology / Q000503:physiopathology / Q000601:surgery; D000315:Adrenalectomy / Q000379:methods; D054369:Agouti-Related Protein; D000818:Animals; D003345:Corticosterone / Q000008:administration & dosage / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000503:physiopathology*; D004343:Drug Implants / Q000494:pharmacology; D005215:Fasting / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D005938:Glucocorticoids / Q000097:blood / Q000502:physiology*; D007031:Hypothalamus / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology*; D007328:Insulin / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009478:Neuropeptide Y / Q000235:genetics; D011333:Pro-Opiomelanocortin / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D054369:Agouti-Related Protein; D004343:Drug Implants; D005938:Glucocorticoids; D007328:Insulin; D036341:Intercellular Signaling Peptides and Proteins; D020738:Leptin; D009478:Neuropeptide Y; D011506:Proteins; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin; D003345:Corticosterone