title: The role of autonomic efferents and uncoupling protein 1 in the glucose-lowering effect of leptin therapy.
abstract: OBJECTIVE
  Leptin reverses hyperglycemia in rodent models of type 1 diabetes (T1D). Direct application of leptin to the brain can lower blood glucose in diabetic rodents, and can activate autonomic efferents and non-shivering thermogenesis in brown adipose tissue (BAT). We investigated whether leptin reverses hyperglycemia through a mechanism that requires autonomic innervation, or uncoupling protein 1 (UCP1)-mediated thermogenesis.
  
  
  METHODS
  To examine the role of parasympathetic and sympathetic efferents in the glucose-lowering action of leptin, mice with a subdiaphragmatic vagotomy or 6-hydroxydopamine induced chemical sympathectomy were injected with streptozotocin (STZ) to induce hyperglycemia, and subsequently leptin treated. To test whether the glucose-lowering action of leptin requires activation of UCP1-mediated thermogenesis in BAT, we administered leptin in STZ-diabetic Ucp1 knockout (Ucp1 (-/-)) mice and wildtype controls.
  
  
  RESULTS
  Leptin ameliorated STZ-induced hyperglycemia in both intact and vagotomised mice. Similarly, mice with a partial chemical sympathectomy did not have an attenuated response to leptin-mediated glucose lowering relative to sham controls, and showed intact leptin-induced Ucp1 expression in BAT. Although leptin activated BAT thermogenesis in STZ-diabetic mice, the anti-diabetic effect of leptin was not blunted in Ucp1 (-/-) mice.
  
  
  CONCLUSIONS
  These results suggest that leptin lowers blood glucose in insulin-deficient diabetes through a manner that does not require parasympathetic or sympathetic innervation, and thus imply that leptin lowers blood glucose through an alternative CNS-mediated mechanism or redundant target tissues. Furthermore, we conclude that the glucose lowering action of leptin is independent of UCP1-dependent thermogenesis.
authors.affiliation: Laboratory of Molecular and Cellular Medicine, 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.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Kwon
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Glavas
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Eva
authors.initials: E
authors.lastname: Tudurí
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Marion
authors.initials: M
authors.lastname: Philippe
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Quong
authors.affiliation: Laboratory of Molecular and Cellular Medicine, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada; Department of Surgery, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: tim.kieffer@ubc.ca.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Kieffer
keywords: 6OHDA, 6-hydroxydopamine; ANS, autonomic nervous system; BAT, brown adipose tissue; Brown adipose tissue; CCK, cholecystokinin; CNS, central nervous system; Glucose; STZ, streptozotocin; Streptozotocin; Sympathectomy; T1D, type 1 diabetes; TH, tyrosine hydroxylase; Type 1 diabetes; UCP1, uncoupling protein 1; Vagotomy; iBAT, interscapular BAT