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 obesityinducing 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.

Margatoxin is a non-selective inhibitor of human Kv1.3 K+ channels

“…05.002 et al, 2006) or obesity and insulin resistance (Upadhyay et al, 2013). K þ channels play a key role in the regulation of the membrane potential of excitable and non-excitable cells (Abbott, 2006;Korn and Trapani, 2005;Varga et al, 2010Varga et al, , 2011.…”

Peptide Fraction pOh2 Exerts Antiadipogenic Activity through Inhibition of C/EBP-αand PPAR-γExpression in 3T3-L1 Adipocytes

“…Snake venom also contains lots of potassium channels blockers [21–23]. ShK-186 significantly reduced weight gain, fat accumulation, and associated inflammation in diet-induced obese mice [24]. Bee venom (BV) has been widely used in the treatment of chronic inflammatory diseases.…”

Developmental expression of Kv1 voltage-gated potassium channels in the avian hypothalamus

“…Future electrophysiology experiments using 4-aminopyridine, a non-selective inhibitor of voltage-gated potassium channels [39], should aid in the confirmation of functional potassium channel subtypes. Furthermore, pharmacological application of venom-derived toxins [40, 41, 42] should confirm the link between specific Kv1 alpha subunit expression and the observed shift in the electrophysiological characteristics of developing hypothalamic neurons.…”