Gonadal Hormones Determine Sensitivity to Central Leptin and Insulin

• Published in: Diabetes (New York, N.Y.) Vol. 55; no. 4; pp. 978 - 987
• Main Authors: CLEGG, Deborah J, BROWN, Lynda M, WOODS, Stephen C, BENOIT, Stephen C
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-04-2006
• Subjects: Animals; Biological and medical sciences; Body fat; Body Weight - drug effects; Care and treatment; Diabetes; Diabetes research; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Energy Intake - drug effects; Estradiol - pharmacology; Estrogens; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; Females; Food; Gender differences; Gonadal disorders; Insulin; Insulin - pharmacology; Laboratory animals; Leptin - pharmacology; Male; Males; Medical sciences; Obesity; Oophorectomy; Orchiectomy; Ovariectomy; Ovaries; Rats; Rats, Long-Evans; Risk factors; Sex Characteristics; Surgery; Endocrinopathy; Pancreatic hormone; Sensitivity; Diabetes mellitus; Leptin; Adipokine; Insulin
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.55.04.06.db05-1339

Gonadal Hormones Determine Sensitivity to Central Leptin and Insulin
Deborah J. Clegg ,
Lynda M. Brown ,
Stephen C. Woods and
Stephen C. Benoit
Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio
Address correspondence and reprint requests to Dr. Deborah J. Clegg, Department of Psychiatry, University of Cincinnati, PO
Box 670559, Cincinatti, OH 45267-0559. E-mail: debbie.clegg{at}uc.edu
Abstract
Males have proportionally more visceral fat and are more likely to develop complications associated with obesity than females,
and the male brain is relatively more sensitive to the catabolic action of insulin and less sensitive to that of leptin than
the female brain. To understand the underlying mechanism, we manipulated estrogen through ovariectomy (OVX) and estradiol
administration. Rats with relatively high systemic estrogen (intact females and OVX females and males administered estrogen
subcutaneously) were significantly more sensitive to leptin’s anorexic action in the brain (i3vt), as well as significantly
less sensitive to insulin’s i3vt action, than intact males. Administering estradiol directly into the brain of our females
increased i3vt leptin sensitivity while decreasing i3vt insulin sensitivity and changed the body fat distribution of our females
to resemble that of intact females. These data indicate that estrogen acts within the brain to increase leptin sensitivity,
decrease insulin sensitivity, and favor subcutaneous over visceral fat.
ER, estrogen receptor
GAPDH, glyceraldehyde-3-phosphate dehydrogenase
i3vt, third cerebral ventricle
OB-Rb, long-form leptin receptor
OVX, ovariectomy
NMR, nuclear magnetic resonance
VMN, ventromedial nucleus
Footnotes
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore
be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Accepted January 17, 2006.
Received October 13, 2005.
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