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Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function.

Publication ,  Journal Article
Barrera, JG; Jones, KR; Herman, JP; D'Alessio, DA; Woods, SC; Seeley, RJ
Published in: J Neurosci
March 9, 2011

Central administration of glucagon-like peptide-1 (GLP-1) causes a dose-dependent reduction in food intake, but the role of endogenous CNS GLP-1 in the regulation of energy balance remains unclear. Here, we tested the hypothesis that CNS GLP-1 activity is required for normal energy balance by using two independent methods to achieve chronic CNS GLP-1 loss of function in rats. Specifically, lentiviral-mediated expression of RNA interference was used to knock down nucleus of the solitary tract (NTS) preproglucagon (PPG), and chronic intracerebroventricular (ICV) infusion of the GLP-1 receptor (GLP-1r) antagonist exendin (9-39) (Ex9) was used to block CNS GLP-1r. NTS PPG knockdown caused hyperphagia and exacerbated high-fat diet (HFD)-induced fat accumulation and glucose intolerance. Moreover, in control virus-treated rats fed the HFD, NTS PPG expression levels correlated positively with fat mass. Chronic ICV Ex9 also caused hyperphagia; however, increased fat accumulation and glucose intolerance occurred regardless of diet. Collectively, these data provide the strongest evidence to date that CNS GLP-1 plays a physiologic role in the long-term regulation of energy balance. Moreover, they suggest that this role is distinct from that of circulating GLP-1 as a short-term satiation signal. Therefore, it may be possible to tailor GLP-1-based therapies for the prevention and/or treatment of obesity.

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Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

March 9, 2011

Volume

31

Issue

10

Start / End Page

3904 / 3913

Location

United States

Related Subject Headings

  • Tissue Culture Techniques
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rats, Long-Evans
  • Rats
  • RNA, Messenger
  • RNA Interference
  • Proglucagon
  • Peptide Fragments
  • Obesity
  • Neurology & Neurosurgery
 

Citation

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Barrera, J. G., Jones, K. R., Herman, J. P., D’Alessio, D. A., Woods, S. C., & Seeley, R. J. (2011). Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. J Neurosci, 31(10), 3904–3913. https://doi.org/10.1523/JNEUROSCI.2212-10.2011
Barrera, Jason G., Kenneth R. Jones, James P. Herman, David A. D’Alessio, Stephen C. Woods, and Randy J. Seeley. “Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function.J Neurosci 31, no. 10 (March 9, 2011): 3904–13. https://doi.org/10.1523/JNEUROSCI.2212-10.2011.
Barrera JG, Jones KR, Herman JP, D’Alessio DA, Woods SC, Seeley RJ. Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. J Neurosci. 2011 Mar 9;31(10):3904–13.
Barrera, Jason G., et al. “Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function.J Neurosci, vol. 31, no. 10, Mar. 2011, pp. 3904–13. Pubmed, doi:10.1523/JNEUROSCI.2212-10.2011.
Barrera JG, Jones KR, Herman JP, D’Alessio DA, Woods SC, Seeley RJ. Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function. J Neurosci. 2011 Mar 9;31(10):3904–3913.

Published In

J Neurosci

DOI

EISSN

1529-2401

Publication Date

March 9, 2011

Volume

31

Issue

10

Start / End Page

3904 / 3913

Location

United States

Related Subject Headings

  • Tissue Culture Techniques
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rats, Long-Evans
  • Rats
  • RNA, Messenger
  • RNA Interference
  • Proglucagon
  • Peptide Fragments
  • Obesity
  • Neurology & Neurosurgery