The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity.
Leptin is required for normal energy and glucose homeostasis. The hypothalamic arcuate nucleus (ARH) has been proposed as an important site of leptin action. To assess the physiological significance of leptin signaling in the ARH, we used mice homozygous for a FLPe-reactivatable, leptin receptor null allele (Lepr(neo/neo) mice). Similar to Lepr(db/db) mice, these mice are obese, hyperglycemic, hyperinsulinemic, infertile, and hypoactive. To selectively restore leptin signaling in the ARH, we generated an adeno-associated virus expressing FLPe-recombinase, which was delivered unilaterally into the hypothalamus using stereotaxic injections. We found that unilateral restoration of leptin signaling in the ARH of Lepr(neo/neo) mice leads to a modest decrease in body weight and food intake. In contrast, unilateral reactivation markedly improved hyperinsulinemia and normalized blood glucose levels and locomotor activity. These data demonstrate that leptin signaling in the ARH is sufficient for mediating leptin's effects on glucose homeostasis and locomotor activity.
Coppari
Roberto
R
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
Ichinose
Masumi
M
Lee
Charlotte E
CE
Pullen
Abigail E
AE
Kenny
Christopher D
CD
McGovern
Robert A
RA
Tang
Vinsee
V
Liu
Shun M
SM
Ludwig
Thomas
T
Chua
Streamson C
SC
Lowell
Bradford B
BB
Elmquist
Joel K
JK
D000483:Alleles; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism*; D001823:Body Composition; D001835:Body Weight; D002467:Cell Nucleus / Q000378:metabolism; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D005298:Fertility; D005947:Glucose / Q000378:metabolism*; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006706:Homeostasis; D006720:Homozygote; D007031:Hypothalamus / Q000378:metabolism*; D007150:Immunohistochemistry; D020738:Leptin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism; D010101:Oxygen Consumption; D011956:Receptors, Cell Surface / Q000378:metabolism; D054411:Receptors, Leptin; D015398:Signal Transduction; D013997:Time Factors
D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D049452:Green Fluorescent Proteins; D004254:DNA Nucleotidyltransferases; C045119:FLP recombinase; D005947:Glucose