Hyperphagia, not hypometabolism, causes early onset obesity in melanocortin-4 receptor knockout mice

Weide, Karin; Christ, Nicole; Moar, Kim-Marie; Arens, Janine; Hinney, Anke; Mercer, Julian G.; Eiden, Sandra; Schmidt, Ingrid

doi:10.1152/physiolgenomics.00129.2002

Cited by 63 publications

(43 citation statements)

References 39 publications

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“…MC4R-null mice and acute block of MC4R by SHU9119 in rats increases meal size and food intake. 23,25,27,36,42 Hyperphagia in MC4R-null mice has been detected as early as P21-P35 by evaluation of cumulative 2-week intake, 25 but daily caloric changes do not become significant until around 14 weeks of age, 36 which is consistent with the results reported here. At 9 weeks of age or approximately P60, the MC4R-null mice did not exhibit statistically significant increases in daily caloric intake over WT or the Kv/MC4R-null mice.…”

Section: Discussionsupporting

confidence: 86%

“…36 Caloric intake was not significantly different across any genotype in comparison to that of WT mice (Figure 5a; not significantly different, ANOVA, SNK). As insignificant differences in caloric intake may become physiologically significant overtime, 25 we also calculated and analyzed a 5-day cumulative food intake ( Figure 5b), but similarly, did not find any genotypic changes. There were also no measurable differences in water consumption at this age ( Figure 5c).…”

Section: Caloric Intake and Water Consumptionmentioning

confidence: 79%

“…23 Genetic deletion of MC4R results in mice that exhibit severe obesity, hyperphagia, hyperinsulinemia, hypometabolism and increased overall growth. 24,25 We generated mice with a double gene-targeted deletion of Kv1.3 and MC4R by interbreeding Kv1.3-null and MC4R-null mouse lines to double homozygosity. Kv1.3 loss from this genetic model of obesity resulted in a reduction in adiposity and body weight that was not due to overall changes in growth but rather the result of increased locomotor activity and energy expenditure (EE).…”

Section: Introductionmentioning

confidence: 99%

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

2008

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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.

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Section: Discussionsupporting

confidence: 86%

Section: Caloric Intake and Water Consumptionmentioning

confidence: 79%

Section: Introductionmentioning

confidence: 99%

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

2008

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“…This could be a consequence of different pathways mediating both roles of melanocortin peptides through MC4 receptors (29, 33). Alternatively, the reduction in oxygen consumption could be an indirect consequence of obesity rather than a direct effect of Pomc deficiency (34). In either case, the drop in energy expenditure contributes to the inability to restore a normal body weight set point.…”

Section: Discussionmentioning

confidence: 99%

Obesity-programmed mice are rescued by early genetic intervention

Bumaschny¹,

Yamashita²,

Casas-Cordero³

et al. 2012

J. Clin. Invest.

125

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Obesity is a chronic metabolic disorder affecting half a billion people worldwide. Major difficulties in managing obesity are the cessation of continued weight loss in patients after an initial period of responsiveness and rebound to pretreatment weight. It is conceivable that chronic weight gain unrelated to physiological needs induces an allostatic regulatory state that defends a supranormal adipose mass despite its maladaptive consequences. To challenge this hypothesis, we generated a reversible genetic mouse model of early-onset hyperphagia and severe obesity by selectively blocking the expression of the proopiomelanocortin gene (Pomc) in hypothalamic neurons. Eutopic reactivation of central POMC transmission at different stages of overweight progression normalized or greatly reduced food intake in these obesity-programmed mice. Hypothalamic Pomc rescue also attenuated comorbidities such as hyperglycemia, hyperinsulinemia, and hepatic steatosis and normalized locomotor activity. However, effectiveness of treatment to normalize body weight and adiposity declined progressively as the level of obesity at the time of Pomc induction increased. Thus, our study using a novel reversible monogenic obesity model reveals the critical importance of early intervention for the prevention of subsequent allostatic overload that auto-perpetuates obesity.

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“…Moreover, in comparison with Mc4r ?/? mice fed a high-fat diet, the Mc4r -/-mice were found to have hyperphagia and altered energy expenditure characterized by decreased diet-induced activity and thermogenesis (Butler et al 2001;Weide et al 2003). Consistent with these results, the Mc4r -/-mice developed hyperphagia when fed a high-fat diet, but not when fed a low-fat diet, providing evidence for a gene-diet interaction in relation to weight gain (Butler and Cone 2003;Sutton et al 2006).…”

Section: Obesity Susceptibility Genes That Interact With Dietary Fatsmentioning

confidence: 62%

The genetics of childhood obesity and interaction with dietary macronutrients

et al. 2013

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The genes contributing to childhood obesity are categorized into three different types based on distinct genetic and phenotypic characteristics. These types of childhood obesity are represented by rare monogenic forms of syndromic or non-syndromic childhood obesity, and common polygenic childhood obesity. In some cases, genetic susceptibility to these forms of childhood obesity may result from different variations of the same gene. Although the prevalence for rare monogenic forms of childhood obesity has not increased in recent times, the prevalence of common childhood obesity has increased in the United States and developing countries throughout the world during the past few decades. A number of recent genome-wide association studies and mouse model studies have established the identification of susceptibility genes contributing to common childhood obesity. Accumulating evidence suggests that this type of childhood obesity represents a complex metabolic disease resulting from an interaction with environmental factors, including dietary macronutrients. The objective of this article is to provide a review on the origins, mechanisms, and health consequences of obesity susceptibility genes and interaction with dietary macronutrients that predispose to childhood obesity. It is proposed that increased knowledge of these obesity susceptibility genes and interaction with dietary macronutrients will provide valuable insight for individual, family, and community preventative lifestyle intervention, and eventually targeted nutritional and medicinal therapies.

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Hyperphagia, not hypometabolism, causes early onset obesity in melanocortin-4 receptor knockout mice

Cited by 63 publications

References 39 publications

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

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

Obesity-programmed mice are rescued by early genetic intervention

The genetics of childhood obesity and interaction with dietary macronutrients

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