Central administration of an endoplasmic reticulum stress inducer inhibits the anorexigenic effects of leptin and insulin

Obesity (Silver Spring). 2009 Oct;17(10):1861-5. doi: 10.1038/oby.2009.194. Epub 2009 Jun 18.


Leptin and insulin are important anorexigenic hormones acting on the hypothalamus. However, most obese humans and animals have reduced hypothalamic responses to leptin and insulin. Increased endoplasmic reticulum (ER) stress has been shown to cause insulin resistance in the livers of obese animals. In the present study, we investigated a role of ER stress in the development of central leptin and insulin resistance. Intracerebroventricular (ICV) administration of the ER stress inducer thapsigargin (TG) increased food intake and body weight. Furthermore, ICV or intra-hypothalamic administration of TG inhibited the anorexigenic and weight-reducing effects of leptin and insulin. ICV administration of TG by itself activated signal-transduction-activated-transcript-3 (STAT3) and Akt in the hypothalamus, but prevented a further activation of hypothalamic STAT3 and Akt by leptin and insulin. We also found that the expression of the ER stress markers such as phosphorylation of the inositol-requiring kinase-1 (IRE1), spliced form of X-box-binding protein-1 (XBP-1s), glucose-regulated/binding immunoglobulin protein-78, and C/EBP homology protein (CHOP) increased in the hypothalami of diet-induced obese (DIO) mice. Furthermore, treatment of chemical chaperone 4-phenyl butylic acid significantly improved central leptin resistance in DIO mice. These findings suggest that increased hypothalamic ER stress in obese animals may induce central leptin and insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • DNA-Binding Proteins / physiology
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / physiology
  • Enzyme Inhibitors / administration & dosage*
  • Hypothalamus / drug effects*
  • Hypothalamus / physiopathology
  • Insulin / physiology*
  • Leptin / antagonists & inhibitors
  • Leptin / physiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy
  • Obesity / physiopathology*
  • Phosphatidylinositol 3-Kinases / physiology
  • RNA / chemistry
  • RNA / genetics
  • Regulatory Factor X Transcription Factors
  • Reverse Transcriptase Polymerase Chain Reaction
  • STAT3 Transcription Factor / physiology
  • Thapsigargin / administration & dosage*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / physiology
  • Transcription Factors / physiology
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Enzyme Inhibitors
  • Insulin
  • Leptin
  • Regulatory Factor X Transcription Factors
  • STAT3 Transcription Factor
  • Stat3 protein, mouse
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Transcription Factor CHOP
  • RNA
  • Thapsigargin
  • Phosphatidylinositol 3-Kinases