Role of Leptin in the Regulation of Glucagon-Like Peptide-1 Secretion
- 1Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- 2Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Glucagon-like peptide-1 (GLP-1), released from intestinal endocrine L cells, is a potent insulinotropic hormone. GLP-1 secretion is diminished in obese patients. Because obesity is linked to abnormal leptin signaling, we hypothesized that leptin may modulate GLP-1 secretion. Leptin significantly stimulated GLP-1 secretion (by up to 250% of control) from fetal rat intestinal cells, a mouse L cell line (GLUTag), and a human L cell line (NCI-H716) in a dose-dependent manner (P < 0.05–0.001). The long form of the leptin receptor was shown to be expressed, and leptin induced the phosphorylation of STAT3 in the three cell types. The leptin receptor was also expressed by rodent and human intestinal L cells, and leptin (1 mg/kg i.p.) significantly stimulated GLP-1 secretion in rats and ob/ob mice. To determine the effect of leptin resistance on GLP-1 secretion, C57BL/6 mice were fed a high-fat (45%) or low-fat (10%) diet for 8 weeks. Mice on the high-fat diet became obese; developed glucose intolerance, hyperinsulinemia, and hyperleptinemia; and were leptin resistant. Mice on the high-fat diet also had twofold lower basal plasma GLP-1 and a diminished GLP-1 response to oral glucose, by 28.5 ± 5.0% (P < 0.05). These results show for the first time that leptin stimulates GLP-1 secretion from rodent and human intestinal L cells, and they suggest that leptin resistance may account for the decreased levels of GLP-1 found in obese humans.
Address correspondence and reprint requests to Dr. Patricia L. Brubaker, Department of Physiology, MSB Room no. 3366, University of Toronto, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada. E-mail:.
Received for publication 24 July 2002 and accepted in revised form 15 October 2002.
ELISA, enzyme-linked immunosorbent assay; FBS, fetal bovine solution; FRIC, fetal rat intestinal cell; GLP-1, glucagon-like peptide-1; GRP, gastrin-releasing peptide; PKC, protein kinase C; PMA, phorbol myristic acid; RIA, radioimmunoassay; TBST, Tris-buffered saline containing 1% Tween 20.