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

Neuron. 2006 Jan 19;49(2):191-203. doi: 10.1016/j.neuron.2005.12.021.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / drug effects
  • Adipose Tissue / physiology
  • Animals
  • Body Composition / drug effects
  • Body Composition / genetics
  • Body Composition / physiology
  • Body Weight / physiology*
  • Diet
  • Electrophysiology
  • Energy Metabolism / drug effects
  • Energy Metabolism / genetics
  • Energy Metabolism / physiology
  • Green Fluorescent Proteins / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology*
  • Homeostasis / drug effects
  • Homeostasis / physiology*
  • Immunohistochemistry
  • In Vitro Techniques
  • Leptin / pharmacology*
  • Male
  • Mice
  • Mice, Transgenic
  • Neurons / drug effects*
  • Obesity / physiopathology
  • Patch-Clamp Techniques
  • Phenotype
  • RNA Probes
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / physiology
  • Receptors, Cytoplasmic and Nuclear / genetics
  • Receptors, Cytoplasmic and Nuclear / physiology*
  • Receptors, Leptin
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Steroidogenic Factor 1
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Ventromedial Hypothalamic Nucleus / cytology
  • Ventromedial Hypothalamic Nucleus / drug effects*

Substances

  • Homeodomain Proteins
  • Leptin
  • RNA Probes
  • Receptors, Cell Surface
  • Receptors, Cytoplasmic and Nuclear
  • Receptors, Leptin
  • STAT3 Transcription Factor
  • Steroidogenic Factor 1
  • Transcription Factors
  • leptin receptor, mouse
  • steroidogenic factor 1, mouse
  • Green Fluorescent Proteins