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

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 darkphase 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.

Selective Kv1.3 channel blocker as therapeutic for obesity and insulin resistance

“…1B). These data corroborate earlier reports that Kv1.3 gene deletion is less effective in reducing weight gain, blood sugar, insulin, leptin, and visceral white adipose tissue (WAT) mass in mice on a normal chow diet compared with those on obesity-inducing diets (8,10). Furthermore, rats fed normal chow diets and treated with ShK-186 (100 μg/kg) also show no reduction in weight gain (20,21).…”

“…Importantly, Kv1.3 −/− mice fed a high-fat diet exhibit increased light-phase metabolism together with reduced weight gain; lower levels of blood sugar, leptin, and insulin; and increased energy expenditure in comparison with wild-type littermates (4-10) (Table S1). Similarly, in melanocortin receptor 4 knockout mice, a genetic model of obesity, Kv1.3 gene deletion increases energy expenditure; decreases adiposity and weight; reduces leptin levels; and extends life span (8). Two mechanisms have been proposed to explain the antiobesity and metabolic effects of Kv1.3 gene deletion: enhanced peripheral insulin sensitization and augmented olfaction.…”

Awake, long-term intranasal insulin treatment does not affect object memory, odor discrimination, or reversal learning in mice

“…Although sex-specific effects have been reported for rats and humans [57, 59, 80, 81], such has not been found for mice [16] so it was not necessary to utilize both sexes. Because mice also demonstrate a lack of diet-induced obesity (DIO) and associated prediabetic state in females [36], with the intent of applying our study for future application for diabetes, it was pragmatic to hone our current study to male mice. Taking the aforementioned into consideration, we acknowledge the potential study limitations due to the lack of females.…”

“…An enzyme-linked immunosorbent assay (ELISA) was performed as per manufacturer’s protocol using the Ultrasensitive Mouse Insulin ELISA (80-INSMSU-E01, ALPCO Salem, NH) and as previously described [36]. In brief, trunk blood was collected at the time of sacrifice and allowed to coagulate at rt for 10 min.…”

Kv1.3: a potential pharmacological target for diabetes

“…For instance, Kv1.3 channels are expressed in postganglionic sympathetic neurons and influence the function of sympathetic activity that regulates body weight and energy homeostasis [16] . The genetargeted deletion of Kv1.3 in a genetic model of obese mice reduced adiposity and total body weight by increasing locomotor activity and thereby total energy expenditure without changing blood glucose and insulin levels [17] . In addition, mice bearing a disrupted Kv1.3 gene had a lower body weight and an increased basal metabolic rate which made them resistant to diet-induced obesity [14] .…”