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Olfactory bulb‐targeted quantum dot (QD) bioconjugate and Kv1.3 blocking peptide improve metabolic health in obese male mice
Author(s) -
Schwartz Austin B.,
Kapur Anshika,
Huang Zhenbo,
Anangi Raveendra,
Spear John M.,
Stagg Scott,
Fardone Erminia,
Dekan Zolan,
Rosenberg Jens T.,
Grant Samuel C.,
King Glenn F.,
Mattoussi Hedi,
Fadool Debra Ann
Publication year - 2021
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.15200
Subject(s) - olfactory bulb , potassium channel , endocrinology , medicine , patch clamp , energy homeostasis , chemistry , insulin , glucose uptake , glucose homeostasis , microbiology and biotechnology , biology , electrophysiology , biophysics , neuroscience , insulin resistance , central nervous system , obesity
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 IC 50, 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.