GLP-1-derived nonapeptide GLP-1(28–36)amide represses hepatic gluconeogenic gene expression and improves pyruvate tolerance in high-fat diet-fed mice

Abstract

T. GLP-1-derived nonapeptide GLP-1(28 -36)amide represses hepatic gluconeogenic gene expression and improves pyruvate tolerance in high-fat diet-fed mice. Certain "degradation" products of GLP-1 were found to possess beneficial effects on metabolic homeostasis. Here, we investigated the function of the COOH-terminal fragment of GLP-1, the nonapeptide GLP-1(28 -36)amide, in hepatic glucose metabolism. C57BL/6 mice fed a highfat diet (HFD) for 13 wk were injected intraperitoneally with GLP-1(28 -36)amide for 6 wk. A significant reduction in body weight gain in response to HFD feeding was observed in GLP-1(28 -36)amidetreated mice. GLP-1(28 -36)amide administration moderately improved glucose disposal during glucose tolerance test but more drastically attenuated glucose production during pyruvate tolerance test, which was associated with reduced hepatic expression of the gluconeogenic genes Pck1, G6pc, and Ppargc1a. Mice treated with GLP-1(28 -36)amide exhibited increased phosphorylation of PKA targets, including cAMP response element-binding protein (CREB), ATF-1, and ␤-catenin. In primary hepatocytes, GLP-1(28 -36)amide reduced glucose production and expression of Pck1, G6pc, and Ppargc1a, which was associated with increased cAMP content and PKA target phosphorylation. These effects were attenuated by PKA inhibition. We suggest that GLP-1(28 -36)amide represses hepatic gluconeogenesis involving the activation of components of the cAMP/PKA signaling pathway. This study further confirmed that GLP-1(28 -36)amide possesses therapeutic potential for diabetes and other metabolic disorders.glucagon-like peptide-1; hepatic glucose production; adenosine 3=,5=-cyclic monophosphate; protein kinase A; type 2 diabetes THE INCRETIN HORMONE GLUCAGON-LIKE PEPTIDE-1 (GLP-1) is secreted by intestinal endocrine L cells upon food intake and hormone regulation (2, 4, 25). GLP-1 stimulates insulin secretion in a glucose concentration-dependent manner and positively regulates pro-insulin gene expression (38) and ␤-cell survival, as well as proliferation of pancreatic ␤-cells (4, 25, 48). Extrapancreatic effects of GLP-1 have also been recognized, including the induction of satiety (47), central regulation of metabolism (18), improvement in cardiac and vascular function (6, 8), reduction in gastric emptying (24), and repression of hepatic glucose production (34), as reviewed in detail elsewhere (4, 48). Owing to its important function in controlling blood glucose homeostasis, two new categories of antidiabetic drugs have been developed in the past decade, namely GLP-1 receptor (GLP-1R) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors, both of which act to increase the activity of GLP-1 signaling to lower plasma glucose levels (4, 48).The active form of GLP-1 is typically considered to be the GLP-1(7-36)amide and GLP-1(7-37) peptides, which are produced from the prohormone proglucagon via the cleavage by the prohormone convertase PC1/3 (11, 31). In the circulation, GLP-1(7-36)amide and GLP-1(7-37) have a very short halflife of aroun...

Liver-Specific Expression of Dominant-Negative Transcription Factor 7-Like 2 Causes Progressive Impairment in Glucose Homeostasis

“…For glucose and pyruvate tolerance tests, mice were fasted for 16 h prior to intraperitoneal injection of either glucose (2 g/kg body wt) or pyruvate (2 g/kg body wt) (38). For the insulin tolerance test, mice were starved for 6 h prior to intraperitoneal insulin (0.75-1.0 units/kg body wt) injection (38).…”

“…For the insulin tolerance test, mice were starved for 6 h prior to intraperitoneal insulin (0.75-1.0 units/kg body wt) injection (38). The method for the glucose production assay has been previously described and is detailed in the Supplementary Experimental Procedures (38).…”

“…Whole-cell lysates were prepared from mouse tissue or cultured cell lines and were subjected to SDS-PAGE, as previously described (38). Antibodies and their sources are listed in Supplementary Experimental Procedures.…”

“…RNA Isolation, Reverse Transcription, and Quantitative PCR Isolation of RNA, cDNA synthesis by reverse transcription, and real-time PCR were performed as previously described (38). Nonquantitative PCR was performed using the Fast DNA Polymerase PCR Mix (Kapa Biosystems) followed by agarose gel electrophoresis.…”

Roux-en-Y Gastric Bypass Improves Hepatic Glucose Metabolism Involving Down-Regulation of Protein Tyrosine Phosphatase 1B in Obese Rats

“…PTTs reflect changes in hepatic glucose production [26]. Therefore, we performed PTTs and found that pyruvate tolerance was dramatically improved by RYGB, but not by sham surgery, in obese rats (p < 0.05) (fig.…”