title: Leptin therapy reverses hyperglycemia in mice with streptozotocin-induced diabetes, independent of hepatic leptin signaling.
abstract: OBJECTIVE
  Leptin therapy has been found to reverse hyperglycemia and prevent mortality in several rodent models of type 1 diabetes. Yet the mechanism of leptin-mediated reversal of hyperglycemia has not been fully defined. The liver is a key organ regulating glucose metabolism and is also a target of leptin action. Thus we hypothesized that exogenous leptin administered to mice with streptozotocin (STZ)-induced diabetes reverses hyperglycemia through direct action on hepatocytes.
  
  
  METHODS
  After the induction of diabetes in mice with a high dose of STZ, recombinant mouse leptin was delivered at a supraphysiological dose for 14 days by an osmotic pump implant. We characterized the effect of leptin administration in C57Bl/6J mice with STZ-induced diabetes and then examined whether leptin therapy could reverse STZ-induced hyperglycemia in mice in which hepatic leptin signaling was specifically disrupted.
  
  
  RESULTS
  Hyperleptinemia reversed hyperglycemia and hyperketonemia in diabetic C57Bl/6J mice and dramatically improved glucose tolerance. These effects were associated with reduced plasma glucagon and growth hormone levels and dramatically enhanced insulin sensitivity, without changes in glucose uptake by skeletal muscle. Leptin therapy also ameliorated STZ-induced hyperglycemia and hyperketonemia in mice with disrupted hepatic leptin signaling to a similar extent as observed in wild-type littermates with STZ-induced diabetes.
  
  
  CONCLUSIONS
  These observations reveal that hyperleptinemia reverses the symptoms of STZ-induced diabetes in mice and that this action does not require direct leptin signaling in the liver.
authors.affiliation: Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Heather C
authors.initials: HC
authors.lastname: Denroche
authors.forename: Jasna
authors.initials: J
authors.lastname: Levi
authors.forename: Rhonda D
authors.initials: RD
authors.lastname: Wideman
authors.forename: Roveena M
authors.initials: RM
authors.lastname: Sequeira
authors.forename: Frank K
authors.initials: FK
authors.lastname: Huynh
authors.forename: Scott D
authors.initials: SD
authors.lastname: Covey
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005934:Glucagon / Q000097:blood; D013006:Growth Hormone / Q000097:blood; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019518:Postprandial Period; D054411:Receptors, Leptin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D001786:Blood Glucose; D020738:Leptin; D054411:Receptors, Leptin; D013006:Growth Hormone; D005934:Glucagon