title: Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance.
abstract: Obesity is an epidemic, calling for innovative and reliable pharmacological strategies. Here, we show that ShK-186, a selective and potent blocker of the voltage-gated Kv1.3 channel, counteracts the negative effects of increased caloric intake in mice fed a diet rich in fat and fructose. ShK-186 reduced weight gain, adiposity, and fatty liver; decreased blood levels of cholesterol, sugar, HbA1c, insulin, and leptin; and enhanced peripheral insulin sensitivity. These changes mimic the effects of Kv1.3 gene deletion. ShK-186 did not alter weight gain in mice on a chow diet, suggesting that the obesity-inducing diet enhances sensitivity to Kv1.3 blockade. Several mechanisms may contribute to the therapeutic benefits of ShK-186. ShK-186 therapy activated brown adipose tissue as evidenced by a doubling of glucose uptake, and increased β-oxidation of fatty acids, glycolysis, fatty acid synthesis, and uncoupling protein 1 expression. Activation of brown adipose tissue manifested as augmented oxygen consumption and energy expenditure, with no change in caloric intake, locomotor activity, or thyroid hormone levels. The obesity diet induced Kv1.3 expression in the liver, and ShK-186 caused profound alterations in energy and lipid metabolism in the liver. This action on the liver may underlie the differential effectiveness of ShK-186 in mice fed a chow vs. an obesity diet. Our results highlight the potential use of Kv1.3 blockers for the treatment of obesity and insulin resistance.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, CA 92697, USA.
authors.forename: Sanjeev Kumar
authors.initials: SK
authors.lastname: Upadhyay
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Eckel-Mahan
authors.forename: M Reza
authors.initials: MR
authors.lastname: Mirbolooki
authors.forename: Indra
authors.initials: I
authors.lastname: Tjong
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Griffey
authors.forename: Galina
authors.initials: G
authors.lastname: Schmunk
authors.forename: Amanda
authors.initials: A
authors.lastname: Koehne
authors.forename: Briac
authors.initials: B
authors.lastname: Halbout
authors.forename: Shawn
authors.initials: S
authors.lastname: Iadonato
authors.forename: Brian
authors.initials: B
authors.lastname: Pedersen
authors.forename: Emiliana
authors.initials: E
authors.lastname: Borrelli
authors.forename: Ping H
authors.initials: PH
authors.lastname: Wang
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Paolo
authors.initials: P
authors.lastname: Sassone-Corsi
authors.forename: K George
authors.initials: KG
authors.lastname: Chandy
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D004032:Diet; D002149:Energy Intake / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D007333:Insulin Resistance; D051664:Kv1.3 Potassium Channel / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D020738:Leptin / Q000097:blood; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009765:Obesity / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects; D011506:Proteins / Q000494:pharmacology*; D015430:Weight Gain / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D051664:Kv1.3 Potassium Channel; D020738:Leptin; D008055:Lipids; D011506:Proteins; C533637:Shk-186 peptide
keywords: brown fat; diabetes mellitus; inflammation; metabolic syndrome; potassium channel