title: Leptin activates a novel CNS mechanism for insulin-independent normalization of severe diabetic hyperglycemia.
abstract: The brain has emerged as a target for the insulin-sensitizing effects of several hormonal and nutrient-related signals. The current studies were undertaken to investigate mechanisms whereby leptin lowers circulating blood glucose levels independently of insulin. After extending previous evidence that leptin infusion directly into the lateral cerebral ventricle ameliorates hyperglycemia in rats with streptozotocin-induced uncontrolled diabetes mellitus, we showed that the underlying mechanism is independent of changes of food intake, urinary glucose excretion, or recovery of pancreatic β-cells. Instead, leptin action in the brain potently suppresses hepatic glucose production while increasing tissue glucose uptake despite persistent, severe insulin deficiency. This leptin action is distinct from its previously reported effect to increase insulin sensitivity in the liver and offers compelling evidence that the brain has the capacity to normalize diabetic hyperglycemia in the presence of sufficient amounts of central nervous system leptin.
authors.affiliation: Department of Medicine, University of Washington at South Lake Union, 815 Mercer Street, N334, PO Box 358055, Seattle, Washington 98195, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: German
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wisse
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Oh-I
authors.forename: David A
authors.initials: DA
authors.lastname: Sarruf
authors.forename: Miles E
authors.initials: ME
authors.lastname: Matsen
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Fischer
authors.forename: Gerald J
authors.initials: GJ
authors.lastname: Taborsky
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D001823:Body Composition / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000378:metabolism*; D003345:Corticosterone / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D005934:Glucagon / Q000097:blood; D005951:Glucose Tolerance Test; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy; D007328:Insulin / Q000494:pharmacology*; D020738:Leptin / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001786:Blood Glucose; D007328:Insulin; D020738:Leptin; D005934:Glucagon; D003345:Corticosterone