title: Amylin improves the effect of leptin on insulin sensitivity in leptin-resistant diet-induced obese mice.
abstract: Leptin enhances insulin sensitivity in addition to reducing food intake and body weight. Recently, amylin, a pancreatic β-cell-derived hormone, was shown to restore a weight-reducing effect of leptin in leptin-resistant diet-induced obesity. However, whether amylin improves the effect of leptin on insulin sensitivity in diet-induced obesity is unclear. Diet-induced obese (DIO) mice were infused with either saline (S), leptin (L; 500 μg·kg⁻¹·day⁻¹), amylin (A; 100 μg·kg⁻¹·day⁻¹), or leptin plus amylin (L/A) for 14 days using osmotic minipumps. Food intake, body weight, metabolic parameters, tissue triglyceride content, and AMP-activated protein kinase (AMPK) activity were examined. Pair-feeding and weight-matched calorie restriction experiments were performed to assess the influence of food intake and body weight reduction. Continuous L/A coadministration significantly reduced food intake, increased energy expenditure, and reduced body weight, whereas administration of L or A alone had no effects. L/A coadministration did not affect blood glucose levels during ad libitum feeding but decreased plasma insulin levels significantly (by 48%), suggesting the enhancement of insulin sensitivity. Insulin tolerance test actually showed the increased effect of insulin in L/A-treated mice. In addition, L/A coadministration significantly decreased tissue triglyceride content and increased AMPKα2 activity in skeletal muscle (by 67%). L/A coadministration enhanced insulin sensitivity more than pair-feeding and weight-matched calorie restriction. In conclusion, this study demonstrates the beneficial effect of L/A coadministration on glucose and lipid metabolism in DIO mice, indicating the possible clinical usefulness of L/A coadministration as a new antidiabetic treatment in obesity-associated diabetes.
authors.affiliation: Dept. of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kusakabe
authors.forename: Ken
authors.initials: K
authors.lastname: Ebihara
authors.forename: Takeru
authors.initials: T
authors.lastname: Sakai
authors.forename: Licht
authors.initials: L
authors.lastname: Miyamoto
authors.forename: Daisuke
authors.initials: D
authors.lastname: Aotani
authors.forename: Yuji
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamamoto-Kataoka
authors.forename: Megumi
authors.initials: M
authors.lastname: Aizawa-Abe
authors.forename: Junji
authors.initials: J
authors.lastname: Fujikura
authors.forename: Kiminori
authors.initials: K
authors.lastname: Hosoda
authors.forename: Kazuwa
authors.initials: K
authors.lastname: Nakao
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000517:prevention & control*; D059305:Diet, High-Fat / Q000009:adverse effects; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D058228:Islet Amyloid Polypeptide / Q000008:administration & dosage / Q000627:therapeutic use*; D020738:Leptin / Q000008:administration & dosage / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D014280:Triglycerides / Q000378:metabolism; D015431:Weight Loss / Q000187:drug effects
chemical_list: D019440:Anti-Obesity Agents; D003692:Delayed-Action Preparations; D007004:Hypoglycemic Agents; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D020738:Leptin; D014280:Triglycerides