Leptin Directly Activates SF1 Neurons in the VMH, and This Action by Leptin Is Required for Normal Body-Weight Homeostasis

• DOI: 10.1016/j.neuron.2005.12.021
• Publication Date: 2006-01-19T19:06:46Z
• Authors: Harveen Dhillon; Jeffrey M. Zigman; Chianping Ye; Charlotte E. Lee; Robert A. McGovern; Vinsee Tang; Christopher D. Kenny; Lauryn M. Christi...; Ryan D. White; Elisabeth A. Edel...; Roberto Coppari; Nina Balthasar; Michael A. Cowley; Streamson Chua; Joel K. Elmquist; Bradford B. Lowell
• Keywords: Leptin; Male; Green Fluorescent Proteins / metabolism; Patch-Clamp Techniques; Receptors, Cell Surface / physiology; HUMDISEASE; Steroidogenic Factor 1; Body Weight / physiology; Mice; Leptin / pharmacology; Homeostasis / physiology; Homeostasis; Signal Transduction / drug effects; Ventromedial Hypothalamic Nucleus / cytology; Neurons; 2. Zero hunger; 0303 health sciences; Immunohistochemistry; Electrophysiology; Phenotype; Adipose Tissue; Body Composition; Receptors, Leptin; Energy Metabolism / drug effects; Signal Transduction / physiology; Energy Metabolism / genetics; STAT3 Transcription Factor / metabolism; Neuroscience(all); Adipose Tissue / drug effects; Neurons / drug effects; Green Fluorescent Proteins; Receptors, Cell Surface / genetics; Ventromedial Hypothalamic Nucleus / drug effects; Mice, Transgenic; In Vitro Techniques; MOLNEURO; 03 medical and health sciences; Transcription Factors / genetics; Body Composition / drug effects; Animals; Receptors, Cytoplasmic and Nuclear / genetics; Obesity; Body Composition / genetics; Homeostasis / drug effects; Homeodomain Proteins / physiology; Homeodomain Proteins; Homeodomain Proteins / genetics; Obesity / physiopathology; Body Weight; RNA Probes; Energy Metabolism / physiology; Diet; Transcription Factors / physiology; Adipose Tissue / physiology; Body Composition / physiology; Receptors, Cytoplasmic and Nuclear / physiology; Energy Metabolism

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.