Liraglutide prevents fast weight gain and β-cell dysfunction in male catch-up growth rats.

Abstract

We reported recently that after a nutritional growth retardation, rats showed significant weight gain, central fat accumulation, dyslipidemia, and β-cell dysfunction during a catch-up growth (CUG) phase. Here, we investigated whether glucagon-like peptide-1 (GLP-1) ameliorated the rapid weight gain, central fat deposition, and β-cell dysfunction during the CUG in rats. Sixty-four male Sprague Dawley rats were stratified into four groups including normal control group, CUG group, catch-up growth with liraglutide treatment group, and catch-up growth with liraglutide and exendin 9-39 treatment group. Energy intake, body weight, and body length were monitored. Fat mass percentage was analyzed by dual energy X-ray absorptiometry scan. Plasma triglyceride and non-esterified fatty acid were measured. The β-cell mass was analyzed by morphometric analysis and signaling molecules were examined by Western blot and real-time PCR. Insulin secretion capability was evaluated by hyperglycemic clamp test. Liraglutide prevented weight gain and improved lipid and glucose metabolism in rats under CUG conditions, which were associated with reduced fasting insulin levels and improved glucose-stimulated insulin secretion. Improved β-cell function is found to be associated with increased β-cell replication as determined by β-cell density and insulin-Ki67 dual staining. Furthermore, liraglutide increased islet pancreatic duodenal homeobox-1 (Pdx-1) and B-cell lymphoma-2 transcript and protein expression, and reduced Procaspase-3 transcript and Caspase-3 p11 subunit protein expression, suggesting that expression of Pdx-1 and reduction of apoptosis may be the mechanisms involved. The therapeutic effects were attenuated in rats co-administered with exendin 9-39, suggesting a GLP-1 receptor-dependent mechanism. These studies revealed that incretin therapy effectively prevented fast weight gain and β-cell dysfunction in rats under conditions of nutrition restriction followed by nutrition excess, which is in part due to enhanced functional β-cell mass and insulin secretory capacity.

• Authors: Juan Zheng, Ting Chen, Ying Zhu, Hui-Qing Li, Xiu-Ling Deng, Qing-Hua Wang, Jiao-Yue Zhang, Lu-Lu Chen
• Journal: Experimental biology and medicine (Maywood, N.J.) (Exp Biol Med (Maywood)) Vol. 240 Issue 9 Pg. 1165-76 (Sep 2015) ISSN: 1535-3699 [Electronic] England
• PMID: 25710926 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by the Society for Experimental Biology and Medicine.

Chemical References

• Fatty Acids, Nonesterified
• Homeodomain Proteins
• Hypoglycemic Agents
• Incretins
• Insulin
• Trans-Activators
• Triglycerides
• pancreatic and duodenal homeobox 1 protein
• Liraglutide

Topics

• Animals
• Caloric Restriction (adverse effects)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Diabetes Mellitus, Type 2 (drug therapy, pathology, physiopathology)
• Fatty Acids, Nonesterified (blood)
• Homeodomain Proteins (genetics, metabolism)
• Hypoglycemic Agents (pharmacology)
• Incretins (pharmacology)
• Insulin (metabolism)
• Insulin Secretion
• Insulin-Secreting Cells (drug effects, metabolism, pathology)
• Liraglutide (pharmacology)
• Male
• Models, Animal
• Obesity, Abdominal (prevention & control)
• Rats
• Rats, Sprague-Dawley
• Trans-Activators (genetics, metabolism)
• Triglycerides (blood)
• Up-Regulation (drug effects)
• Weight Gain (drug effects, physiology)