An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

Mar 4, 2008Gastroenterology

An albumin-linked exendin-4 affects brain and body systems controlling mouse energy use and blood sugar

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Abstract

CJC-1134-PC acutely lowered blood glucose levels in wild-type mice and improved glucose tolerance after 4 weeks of treatment.

CJC-1134-PC activated GLP-1 receptor signaling in specific cell types.
The compound rapidly activated certain brain regions responsible for regulating gastric emptying and appetite.
Acute administration of CJC-1134-PC inhibited gastric emptying and reduced food intake in a manner dependent on the GLP-1 receptor.
Chronic treatment in mice on a high-fat diet resulted in improved glucose tolerance and increased insulin levels.
Weight loss and decreased liver fat content were also observed following 4 weeks of CJC-1134-PC treatment.

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BACKGROUND & AIMS: Glucagon-like peptide-1 (GLP-1) regulates glucose homeostasis through multiple mechanisms including direct actions on the endocrine pancreas and indirect activation of central nervous system circuits regulating gastric emptying, satiety, and body weight. Because native GLP-1 is rapidly degraded, there is considerable interest in development of more potent GLP-1 receptor (GLP-1R) agonists with sustained activity; however, the extent to which much larger GLP-1R agonists will mimic some or all of the actions of smaller peptides remains uncertain.

METHODS: We studied the actions of CJC-1134-PC, a recombinant human serum albumin-exendin-4 conjugated protein, at the GLP-1R using heterologous cells expressing the GLP-1R in vitro and both wild-type and Glp1r(-/-) mice in vivo.

RESULTS: CJC-1134-PC activated GLP-1R-dependent signaling in baby hamster kidney-GLP-1R cells and acutely lowered blood glucose in wild-type but not in Glp1r(-/-) mice. Moreover, acute administration of CJC-1134-PC rapidly activated c-Fos expression in multiple regions of the central nervous system, acutely inhibited gastric emptying, and produced sustained inhibition of food intake in a GLP-1R-dependent manner. Furthermore, chronic daily treatment of high-fat diet-fed wild-type mice with CJC-1134-PC for 4 weeks led to improved glucose tolerance, increased levels of glucose-stimulated insulin, decreased HbA1c, and weight loss associated with decreased hepatic triglyceride content.

CONCLUSIONS: These findings illustrate that a high-molecular-weight exendin-4-albumin conjugate retains the ability to mimic a full spectrum of GLP-1R-dependent actions, including activation of central nervous system circuits regulating gastric emptying, food intake, and body weight.

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An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

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