Hyperphagia and increased fat accumulation in two models of chronic CNS glucagon-like peptide-1 loss of function.
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.
Duke Scholars
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- Tissue Culture Techniques
- Reverse Transcriptase Polymerase Chain Reaction
- Rats, Long-Evans
- Rats
- RNA, Messenger
- RNA Interference
- Proglucagon
- Peptide Fragments
- Obesity
- Neurology & Neurosurgery
Citation
Published In
DOI
EISSN
Publication Date
Volume
Issue
Start / End Page
Location
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