title: GLP-1(32-36)amide Pentapeptide Increases Basal Energy Expenditure and Inhibits Weight Gain in Obese Mice.
abstract: The prevalence of obesity-related diabetes is increasing worldwide. Here we report the identification of a pentapeptide, GLP-1(32-36)amide (LVKGRamide), derived from the glucoincretin hormone GLP-1, that increases basal energy expenditure and curtails the development of obesity, insulin resistance, diabetes, and hepatic steatosis in diet-induced obese mice. The pentapeptide inhibited weight gain, reduced fat mass without change in energy intake, and increased basal energy expenditure independent of physical activity. Analyses of tissues from peptide-treated mice reveal increased expression of UCP-1 and UCP-3 in brown adipose tissue and increased UCP-3 and inhibition of acetyl-CoA carboxylase in skeletal muscle, findings consistent with increased fatty acid oxidation and thermogenesis. In palmitate-treated C2C12 skeletal myotubes, GLP-1(32-36)amide activated AMPK and inhibited acetyl-CoA carboxylase, suggesting activation of fat metabolism in response to energy depletion. By mass spectroscopy, the pentapeptide is rapidly formed from GLP-1(9-36)amide, the major form of GLP-1 in the circulation of mice. These findings suggest that the reported insulin-like actions of GLP-1 receptor agonists that occur independently of the GLP-1 receptor might be mediated by the pentapeptide, and the previously reported nonapeptide (FIAWLVKGRamide). We propose that by increasing basal energy expenditure, GLP-1(32-36)amide might be a useful treatment for human obesity and associated metabolic disorders.
authors: Laboratory of Molecular Endocrinology and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: Eva
authors: E
authors: Tomas
authors: Laboratory of Molecular Endocrinology and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: Violeta
authors: V
authors: Stanojevic
authors: Laboratory of Molecular Endocrinology and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: Karen
authors: K
authors: McManus
authors: Laboratory of Molecular Endocrinology and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: Ashok
authors: A
authors: Khatri
authors: Department of Biochemistry, Tufts University, Boston, MA.
authors: Paul
authors: P
authors: Everill
authors: Department of Biochemistry, Tufts University, Boston, MA.
authors: William W
authors: WW
authors: Bachovchin
authors: Laboratory of Molecular Endocrinology and Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA jhabener@partners.org.
authors: Joel F
authors: JF
authors: Habener
mesh_terms: D000818:Animals; D001481:Basal Metabolism / Q000187:drug effects*; D002478:Cells, Cultured; D059305:Diet, High-Fat; D004734:Energy Metabolism / Q000187:drug effects*; D005227:Fatty Acids / Q000378:metabolism; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology*; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D006946:Hyperinsulinism / Q000188:drug therapy; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects*
chemical_list: D005227:Fatty Acids; C000598373:GLP-1(32-36)amide; D052216:Glucagon-Like Peptide 1