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. 2008 Aug;32(8):1222-32.
doi: 10.1038/ijo.2008.77. 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

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Free PMC article

Kv1.3 Gene-Targeted Deletion Alters Longevity and Reduces Adiposity by Increasing Locomotion and Metabolism in melanocortin-4 Receptor-Null Mice

K Tucker et al. Int J Obes (Lond). .
Free PMC article

Abstract

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.

Figures

Figure 1
Figure 1
Developmental total body weight is dependent upon genotype. (a) Line graph plot of daily (Postnatal day10 (P10) to P50), then weekly, body weight for wild-type mice (WT, n = 6), Kv1.3 knockout (Kv-null, n = 9), melanocortin-4 receptor knockout (MC4R-null, n = 6) and double-knockout mice (Kv/MC4R-null, n = 16). (b) Bar graph representation of total body weight over age in months. Different letters within an age group indicate a significant difference at the 95% percentile as determined by a one-way analysis of variance (ANOVA; treatment = genotype) using a Student–Newman–Keuls (SNK) post hoc test. (a,b) Data represent mean standard error of the mean (s.e.m.) in this and all subsequent figures.
Figure 2
Figure 2
Gender-specific body weight is dependent upon genotype. Graphing and abbreviation as in Figure 1a, but sorted by sex. The dashed box (P60–P75) indicates initial separation in genotype-dependent weight changes and represents bracketed age group upon which all subsequent experiments were performed (Figure 3–Figure 7). Note the higher variability and early weight divergence in female (a) when compared to male (b) mice. Plotted sample size: (a) female (wild type, WT, n = 2; Kv-null, n = 3; melanocortin-4 receptor-null mouse, MC4R-null, n = 2; Kv/MC4R-null, n = 8). (b) Male (WT, n = 4; Kv-null, n = 5; MC4R-null, n = 3; Kv/MC4R-null, n = 8).
Figure 3
Figure 3
Body weight, growth and adiposity are dependent upon genotype. Histogram plot of (a) mean body weight, (b) nose to anus length, and (c) female, or (d) male fat pad deposition sorted by genotype. Abbreviations as in Figure 1. n, number of animals; Endo, Endometrial; Epidid, epididimal; Mesen, mesenteric; Retro, retroperitoneal; Sub-Q, subcutaneous; Brown, brown fat. Different lowercase letters denote a significant difference within females and different capital letters indicate a significant difference within males at the 95% percentile as determined by a one-way analysis of variance (ANOVA; treatment = genotype) followed by a Student–Newman–Keuls (SNK) post hoc test. Statistics for (c) and (d) are for within fat pad comparison (treatment = genotype).
Figure 4
Figure 4
Fasting blood chemistry is dependent upon genotype. Histogram plot of fasting (a) blood glucose, (b) insulin and (c) leptin determined following a 12 h, dark-phase fast. Abbreviations, statistical treatment as per Figure 1.
Figure 5
Figure 5
Daily caloric and water intake is not dependent upon genotype. Histogram plot of (a) daily caloric intake, (b) 5-day cumulative caloric intake and (c) water intake. Data represent mean ± s.e.m. of 2-day interval (a,c) or 5-day cumulative caloric intake (b) preceded by a 5-day acclimation period. Abbreviations, statistical treatment as per Figure 1.
Figure 6
Figure 6
Metabolically active mass-specific metabolic activity and locomotor activity are dependent on genotype. Mice were monitored for 8 days in custom-built metabolic chambers that monitor oxygen consumption (VO2) and locomotor activity. Histogram plot of (a) dark-phase or (b) light-phase metabolically active mass-specific VO2 and dark-phase(c) or light-phase (d) locomotor activity. Data represent mean ± s.e.m. of 2-day interval preceded by a 5-day acclimation period. Abbreviations, statistical treatment as per Figure 1.
Figure 7
Figure 7
Mass-specific total energy expenditure (TEE) is dependent upon genotype. Histogram plot of the mean (a) mass-specific TEE, (b) dark-phase and (c) light-phase mass-specific energy expenditure sorted by sex and genotype. Data represent mean ± s.e.m. of 2-day interval preceded by a 5-day acclimation period. Abbreviations, statistical treatment as per Figure 1. Mass-specific TEE was calculated as the sum of the 12 h dark-phase and 11 h light-phase energy expenditure, determined by Weir equation, divided by the animal weight (see ‘Materials and methods’ for details).
Figure 8
Figure 8
Kv1.3 gene-targeted deletion improves longevity and fecundity. Histogram plot of the mean (a) longevity and (c) pregnancy rate calculated as total number of births/total number of crosses for each genotype. Data represent mean ± s.e.m. Abbreviations, statistical treatment as per Figure 1. Survival curve (b) depicting the percent survival at various ages. Note the median age of survival for wild type (WT) is 28 months, Kv-null is 32 months, melanocortin-4 receptor-null mouse (MC4R-null) is 18 months and Kv/MC4R-null mice is 22 months.

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