GLP-1-derived nonapeptide GLP-1(28–36)amide inhibits weight gain and attenuates diabetes and hepatic steatosis in diet-induced obese mice

The metabolic syndrome is an obesity-associated disease manifested as severe insulin resistance, hyperlipidemia, hepatic steatosis, and diabetes. Previously we proposed that a nonapeptide, FIAWLVKGRamide, GLP-1(28–36)amide, derived from the gluco-incretin hormone, glucagon-like peptide-1 (GLP-1), might have insulin-like actions. Recently, we reported that the nonapeptide appears to enter hepatocytes, target to mitochondria, and suppress glucose production and reactive oxygen species. Therefore, the effects of GLP-1(28–36)amide were examined in diet-induced obese, insulin-resistant mice as a model for the development of human metabolic syndrome. Three- to 11-week infusions of GLP-1(28–36)amide were administered via osmopumps to mice fed a very high fat diet (VHFD) and to control mice on a normal low fat diet (LFD). Body weight, DXA, energy intake, plasma insulin and glucose, and liver triglyceride levels were assessed. GLP-1(28–36)amide inhibited weight gain, accumulation of liver triglycerides, and improved insulin sensitivity by attenuating the development of fasting hyperglycemia and hyperinsulinemia in mice fed VHFD. GLP-1(28–36)amide had no observable effects in control LFD mice. Surprisingly, the energy intake of peptide-infused obese mice is 25–70% greater than in obese mice receiving vehicle alone, yet did not gain excess weight. GLP-1(28–36)amide exerts insulin-like actions selectively in conditions of obesity and insulin resistance. The peptide curtails weight gain in diet-induced obese mice in the face of an increase in energy intake suggesting increased energy expenditure. These findings suggest utility of GLP-1(28–36)amide, or a peptide mimetic derived there from, for the treatment of insulin resistance and the metabolic syndrome. ► GLP-1(28–36)amide, derived from GLP-1, has insulin-like actions in obese mice. ► The nonapeptide inhibits weight gain and the development of insulin resistance. ► It also attenuates diabetes and hepatic steatosis. ► No effects of GLP-1(28–36)amide are seen in normal lean, insulin-sensitive mice. ► GLP-1(28–36)amide might be a treatment for metabolic syndrome.