Leucine deprivation stimulates fat loss via increasing CRH expression in the hypothalamus and activating the sympathetic nervous system

Mol Endocrinol. 2011 Sep;25(9):1624-35. doi: 10.1210/me.2011-0028. Epub 2011 Jun 30.


We previously showed that leucine deprivation decreases abdominal fat mass largely by increasing energy expenditure, as demonstrated by increased lipolysis in white adipose tissue (WAT) and uncoupling protein 1 (UCP1) expression in brown adipose tissue (BAT). The goal of the present study was to investigate the possible involvement of central nervous system (CNS) in this regulation and elucidate underlying molecular mechanisms. For this purpose, levels of genes and proteins related to lipolysis in WAT and UCP1 expression in BAT were analyzed in wild-type mice after intracerebroventricular administration of leucine or corticotrophin-releasing hormone antibodies, or in mice deleted for three β-adrenergic receptors, after being maintained on a leucine-deficient diet for 7 d. Here, we show that intracerebroventricular administration of leucine significantly attenuates abdominal fat loss and blocks activation of hormone sensitive lipase in WAT and induction of UCP1 in BAT in leucine-deprived mice. Furthermore, we provide evidence that leucine deprivation stimulates fat loss by increasing expression of corticotrophin-releasing hormone in the hypothalamus via activation of stimulatory G protein/cAMP/protein kinase A/cAMP response element-binding protein pathway. Finally, we show that the effect of leucine deprivation on fat loss is mediated by activation of the sympathetic nervous system. These results suggest that CNS plays an important role in regulating fat loss under leucine deprivation and thereby provide novel and important insights concerning the importance of CNS leucine in the regulation of energy homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abdominal Fat / drug effects
  • Abdominal Fat / metabolism
  • Adipose Tissue, Brown / metabolism
  • Adiposity* / drug effects
  • Animals
  • Antibodies / administration & dosage
  • Antibodies / pharmacology
  • Corticotropin-Releasing Hormone / immunology
  • Corticotropin-Releasing Hormone / metabolism*
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Energy Metabolism / drug effects
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Hypothalamus / drug effects
  • Hypothalamus / enzymology
  • Hypothalamus / metabolism*
  • Injections, Intraventricular
  • Leucine / administration & dosage
  • Leucine / deficiency*
  • Leucine / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, beta / deficiency
  • Receptors, Adrenergic, beta / metabolism
  • Signal Transduction / drug effects
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / metabolism*


  • Antibodies
  • Cyclic AMP Response Element-Binding Protein
  • Receptors, Adrenergic, beta
  • Corticotropin-Releasing Hormone
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • GTP-Binding Protein alpha Subunits, Gs
  • Leucine