Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis.
Leptin, an adipocyte-derived hormone, acts directly on the brain to control food intake and energy expenditure. An important question is the identity of first-order neurons initiating leptin's anti-obesity effects. A widely held view is that most, if not all, of leptin's effects are mediated by neurons located in the arcuate nucleus of the hypothalamus. However, leptin receptors (LEPRs) are expressed in other sites as well, including the ventromedial hypothalamus (VMH). The possible role of leptin acting in "nonarcuate" sites has largely been ignored. In the present study, we show that leptin depolarizes and increases the firing rate of steroidogenic factor-1 (SF1)-positive neurons in the VMH. We also show, by generating mice that lack LEPRs on SF1-positive neurons, that leptin action at this site plays an important role in reducing body weight and, of note, in resisting diet-induced obesity. These results reveal a critical role for leptin action on VMH neurons.
Dhillon
Harveen
H
Department of Medicine, Division of Endocrinology, Program in Neuroscience, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
Zigman
Jeffrey M
JM
Ye
Chianping
C
Lee
Charlotte E
CE
McGovern
Robert A
RA
Tang
Vinsee
V
Kenny
Christopher D
CD
Christiansen
Lauryn M
LM
White
Ryan D
RD
Edelstein
Elisabeth A
EA
Coppari
Roberto
R
Balthasar
Nina
N
Cowley
Michael A
MA
Chua
Streamson
S
Elmquist
Joel K
JK
Lowell
Bradford B
BB
D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology; D000818:Animals; D001823:Body Composition / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D001835:Body Weight / Q000502:physiology*; D004032:Diet; D004594:Electrophysiology; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000502:physiology*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects*; D009765:Obesity / Q000503:physiopathology; D018408:Patch-Clamp Techniques; D010641:Phenotype; D015347:RNA Probes; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D054339:Steroidogenic Factor 1; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014697:Ventromedial Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects*
D018398:Homeodomain Proteins; D020738:Leptin; D015347:RNA Probes; D011956:Receptors, Cell Surface; D018160:Receptors, Cytoplasmic and Nuclear; D054411:Receptors, Leptin; D050796:STAT3 Transcription Factor; D054339:Steroidogenic Factor 1; D014157:Transcription Factors; C515447:leptin receptor, mouse; C515058:steroidogenic factor 1, mouse; D049452:Green Fluorescent Proteins