Kv1.3 gene-targeted deletion alters longevity and reduces adiposity by increasing locomotion and metabolism in melanocortin-4 receptor-null mice.
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).


METHODS
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.
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
K
K
Tucker
J M
JM
Overton
D A
DA
Fadool
D050154:Adiposity / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002153:Calorimetry, Indirect / Q000379:methods; D004195:Disease Models, Animal; D004326:Drinking / Q000235:genetics; D002149:Energy Intake / Q000235:genetics; D005260:Female; D005298:Fertility / Q000235:genetics; D017353:Gene Deletion; D006128:Growth / Q000235:genetics; D006706:Homeostasis / Q000235:genetics; D007328:Insulin / Q000097:blood; D051664:Kv1.3 Potassium Channel / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D020738:Leptin / Q000097:blood; D008124:Locomotion / Q000235:genetics*; D008136:Longevity / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control; D010101:Oxygen Consumption / Q000235:genetics; D044105:Receptor, Melanocortin, Type 4 / Q000172:deficiency / Q000235:genetics* / Q000502:physiology; D015430:Weight Gain / Q000235:genetics
D001786:Blood Glucose; D007328:Insulin; D051664:Kv1.3 Potassium Channel; D020738:Leptin; D044105:Receptor, Melanocortin, Type 4