Olfactory bulb‐targeted quantum dot (QD) bioconjugate and Kv1.3 blocking peptide improve metabolic health in obese male mice

Abstract

The olfactory system is a driver of feeding behavior, whereby olfactory acuity is modulated by the metabolic state of the individual. The excitability of the major output neurons of the olfactory bulb (OB) can be modulated through targeting a voltage‐dependent potassium channel, Kv1.3, which responds to changes in metabolic factors such as insulin, glucose, and glucagon‐like peptide‐1. Because gene‐targeted deletion or inhibition of Kv1.3 in the periphery has been found to increase energy metabolism and decrease body weight, we hypothesized that inhibition of Kv1.3 selectively in the OB could enhance excitability of the output neurons to evoke changes in energy homeostasis. We thereby employed metal‐histidine coordination to self‐assemble the Kv1.3 inhibitor margatoxin (MgTx) to fluorescent quantum dots (QDMgTx) as a means to label cells in vivo and test changes in neuronal excitability and metabolism when delivered to the OB. Using patch‐clamp electrophysiology to measure Kv1.3 properties in heterologously expressed cells and native mitral cells in OB slices, we found that QDMgTx had a fast rate of inhibition, but with a reduced IC50, and increased action potential firing frequency. QDMgTx was capable of labeling cloned Kv1.3 channels but was not visible when delivered to native Kv1.3 in the OB. Diet‐induced obese mice were observed to reduce body weight and clear glucose more quickly following osmotic mini‐pump delivery of QDMgTx/MgTx to the OB, and following MgTx delivery, they increased the use of fats as fuels (reduced respiratory exchange ratio). These results suggest that enhanced excitability of bulbar output neurons can drive metabolic responses.

Consumption of dietary fat causes loss of olfactory sensory neurons and associated circuitry that is not mitigated by voluntary exercise in mice

“…While our interpretation cannot directly include olfactory ability (we cannot assume loss of OSNs = loss of olfactory ability), we and others have previously shown a relationship between metabolism and olfactory ability (Fadool et al 2004;Riera et al 2017). Kv1.3 −/− mice are notably super-smellers in terms of olfactory discrimination and threshold, are thin and are resistant to DIO (Xu et al 2003b(Xu et al , 2004Upadyay et al 2013;Thiebaud et al 2014;Riera et al 2017), and blocking Kv1.3 in the olfactory bulb causes a reduction in RER in the light cycle (Schwartz et al 2021). Mice with loss of olfactory ability due to genetic ablation of OSNs were found to have an increase in EE and be resistant to DIO (Riera et al 2017).…”

“…2017), and blocking Kv1.3 in the olfactory bulb causes a reduction in RER in the light cycle (Schwartz et al . 2021). Mice with loss of olfactory ability due to genetic ablation of OSNs were found to have an increase in EE and be resistant to DIO (Riera et al .…”

Optimization of Pichia pastoris Expression System for High-Level Production of Margatoxin

“…Similarly, the Kv1.3 selectivity of HsTx1 over Kv1.1 was improved significantly by R14A substitution ( Rashid et al, 2014 ). In addition, peptide toxins are widely used to investigate the function of Kv1.x ion channels in various cell types in vivo as well as in vitro ( Erdogan et al, 2005 ; Tubert et al, 2016 ; Schwartz et al, 2020 ; Toldi et al, 2020 ). Obviously, one needs a reliable and economical system to produce an ample amount of these peptide toxins and their analogs to develop them as therapeutic drugs for the treatment of autoimmune disorders and to study the physiological role of ion channels.…”

GLP-1 Suppresses Feeding Behaviors and Modulates Neuronal Electrophysiological Properties in Multiple Brain Regions

“…The olfactory acuity is regulated by the metabolic state and therefore the olfactory system is a driver of feeding behavior. Enhancement of neuronal excitability of the major output neurons of the olfactory bulb via blocking voltage-dependent potassium channel reduces body weight in obese mice (Schwartz et al, 2021). Previous study suggested that chronic administration of fat in the diet impairs the spontaneous firing rate of MCs (Fadool et al, 2011), and reduces the amplitude of electro-olfactogram (EOG).…”