Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice.
Leptin action on its receptor (LEPR) stimulates energy expenditure and reduces food intake, thereby lowering body weight. One leptin-sensitive target cell mediating these effects on energy balance is the proopiomelano-cortin (POMC) neuron. Recent evidence suggests that the action of leptin on POMC neurons regulates glucose homeostasis independently of its effects on energy balance. Here, we have dissected the physiological impact of direct leptin action on POMC neurons using a mouse model in which endogenous LEPR expression was prevented by a LoxP-flanked transcription blocker (loxTB), but could be reactivated by Cre recombinase. Mice homozygous for the Lepr(loxTB) allele were obese and exhibited defects characteristic of LEPR deficiency. Reexpression of LEPR only in POMC neurons in the arcuate nucleus of the hypothalamus did not reduce food intake, but partially normalized energy expenditure and modestly reduced body weight. Despite the moderate effects on energy balance and independent of changes in body weight, restoring LEPR in POMC neurons normalized blood glucose and ameliorated hepatic insulin resistance, hyperglucagonemia, and dyslipidemia. Collectively, these results demonstrate that direct leptin action on POMC neurons does not reduce food intake, but is sufficient to normalize glucose and glucagon levels in mice otherwise lacking LEPR.
Division of Hypothalamic Research, Department of Internal Medicine, University of Texas Southwestern Medical School, Dallas, Texas 75390-9051, USA.
Eric D
ED
Berglund
Claudia R
CR
Vianna
Jose
J
Donato
Mi Hwa
MH
Kim
Jen-Chieh
JC
Chuang
Charlotte E
CE
Lee
Danielle A
DA
Lauzon
Peagan
P
Lin
Laura J
LJ
Brule
Michael M
MM
Scott
Roberto
R
Coppari
Joel K
JK
Elmquist
D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D001835:Body Weight; D004734:Energy Metabolism; D005260:Female; D005934:Glucagon / Q000737:chemistry; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006720:Homozygote; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism*; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D054411:Receptors, Leptin / Q000378:metabolism
D007328:Insulin; D020738:Leptin; D054411:Receptors, Leptin; D011333:Pro-Opiomelanocortin; D005934:Glucagon; D005947:Glucose