Direct insulin and leptin action on pro-opiomelanocortin neurons is required for normal glucose homeostasis and fertility.
Circulating leptin and insulin convey information regarding energy stores to the central nervous system, particularly the hypothalamus. Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy balance and glucose homeostasis and express leptin and insulin receptors. However, the physiological significance of concomitant leptin and insulin action on POMC neurons remains to be established. Here, we show that mice lacking both leptin and insulin receptors in POMC neurons (Pomc-Cre, Lepr(flox/flox) IR(flox/flox) mice) display systemic insulin resistance, which is distinct from the single deletion of either receptor. In addition, Pomc-Cre, Lepr(flox/flox) IR(flox/flox) female mice display elevated serum testosterone levels and ovarian abnormalities, resulting in reduced fertility. We conclude that direct action of insulin and leptin on POMC neurons is required to maintain normal glucose homeostasis and reproductive function.
Hill
Jennifer W
JW
Center for Diabetes and Endocrine Research, Department of Physiology and Pharmacology, College of Medicine, The University of Toledo, Toledo, OH 43614, USA.
Elias
Carol F
CF
Fukuda
Makoto
M
Williams
Kevin W
KW
Berglund
Eric D
ED
Holland
William L
WL
Cho
You-Ree
YR
Chuang
Jen-Chieh
JC
Xu
Yong
Y
Choi
Michelle
M
Lauzon
Danielle
D
Lee
Charlotte E
CE
Coppari
Roberto
R
Richardson
James A
JA
Zigman
Jeffrey M
JM
Chua
Streamson
S
Scherer
Philipp E
PE
Lowell
Bradford B
BB
Brüning
Jens C
JC
Elmquist
Joel K
JK
D000704:Analysis of Variance; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D005260:Female; D005298:Fertility / Q000502:physiology*; D006706:Homeostasis / Q000502:physiology*; D007031:Hypothalamus / Q000166:cytology / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D013739:Testosterone / Q000097:blood
D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D013739:Testosterone; D011333:Pro-Opiomelanocortin