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Int J Obes (Lond). 2008 Aug;32( :1222-32. Epub 2008 Jun 10.
Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by
increasing locomotion and metabolism in melanocortin-4 receptor-null
mice.
Tucker K, Overton JM, Fadool DA.
Department of Biological Science, Florida State University, Tallahassee,
FL 32306, USA.
OBJECTIVE: Gene-targeted deletion of the voltage-gated potassium
channel, Kv1.3, results in 'super-smeller' mice that have altered firing
patterns of mitral cells in the olfactory bulb, modified axonal
targeting to glomerular synaptic units, and behaviorally have an
increased ability to detect and discriminate odors. Moreover, the
Kv1.3-null mice weighed less than their wild-type counterparts, have
modified ingestive behaviors, and are resistant to fat deposition
following a moderately high-fat dietary regime. In this study, we
investigate whether or not gene-targeted deletion of Kv1.3 (Shaker
family member) can abrogate weight gain in a genetic model of obesity,
the melanocortin-4 receptor-null mouse (MC4R-null). DESIGN: Mice with
double gene-targeted deletions of Kv1.3 and MC4R were generated by
interbreeding Kv1.3 (Kv)- and MC4R-null mouse lines to homozygosity.
Developmental weights, nose to anus length, fat pad weight, fasting
serum chemistry, oxygen consumption, carbon dioxide respiration,
locomotor activity and caloric intake were monitored in control,
Kv-null, MC4R-null and Kv/MC4R-null mice. Physiological and metabolic
profiles were acquired at postnatal day 60 (P60) in order to explore
changes linked to body weight at the reported onset of obesity in the
MC4R-null model. RESULTS: Gene-targeted deletion of Kv1.3 in MC4R-null
mice reduces body weight by decreasing fat deposition and subsequent
fasting leptin levels, without changing the overall growth, fasting
blood glucose or serum insulin. Gene-targeted deletion of Kv1.3 in
MC4R-null mice significantly extended lifespan and increased
reproductive success. Basal or light-phase mass-specific metabolic rate
and locomotor activity were not affected by genetic deletion of Kv1.3 in
MC4R-null mice but dark-phase locomotor activity and mass-specific
metabolism were significantly increased resulting in increased total
energy expenditure. CONCLUSIONS: Gene-targeted deletion of Kv1.3 can
reduce adiposity and total body weight in a genetic model of obesity by
increasing both locomotor activity and mass-specific metabolism.
Publication Types:
* Research Support, N.I.H., Extramural
* Research Support, Non-U.S. Gov't
PMID: 18542083 |
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