Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

Sanjeev Kumar Upadhyay, Kristin L. Eckel-Mahan, M. Reza Mirbolooki, Indra Tjong, Stephen M Griffey, Galina Schmunk, Amanda Koehne, Briac Halbout, Shawn Iadonato, Brian Pedersen, Emiliana Borrelli, Ping H. Wang, Jogeshwar Mukherjee, Paolo Sassone-Corsi, K. George Chandy

Research output: Contribution to journalArticle

43 Scopus citations

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 tissuemanifested 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 livermay underlie the differential effectiveness of ShK-186 inmice 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.

Original languageEnglish (US)
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number24
DOIs
StatePublished - Jun 11 2013

Keywords

  • Brown fat
  • Diabetes mellitus
  • Inflammation
  • Metabolic syndrome
  • Potassium channel

ASJC Scopus subject areas

  • General

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    Upadhyay, S. K., Eckel-Mahan, K. L., Mirbolooki, M. R., Tjong, I., Griffey, S. M., Schmunk, G., Koehne, A., Halbout, B., Iadonato, S., Pedersen, B., Borrelli, E., Wang, P. H., Mukherjee, J., Sassone-Corsi, P., & Chandy, K. G. (2013). Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance. Proceedings of the National Academy of Sciences of the United States of America, 110(24). https://doi.org/10.1073/pnas.1221206110