Western diet increases wheel running in mice selectively bred for high voluntary wheel running

Meek, Thomas H.; Eisenmann, Joey C.; Garland, Theodore

doi:10.1038/ijo.2010.25

Cited by 59 publications

(70 citation statements)

References 59 publications

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“…In contrast, several findings in the Myh4 knockout strain do not closely match data from mini-muscle mice. For example, mini-muscle mice have longer tibiafibulae (Kelly et al 2006), eat more food per gram of body mass (Meek et al 2010), have disorganized muscle fibers in certain muscle regions (Guderley et al 2006(Guderley et al , 2008, and have reduced contractile speed (Syme et al 2005;McGillivray et al 2009), whereas none of those alterations have been reported in the Myh4 knockout mice. Some of the differences between the mice may be attributable to context (specific muscle studied, age, sex, rearing environment), while others may be due to the different types of mutations (null in the knockout and likely hypomorphic in the minimuscle mice.…”

Section: Discussionmentioning

confidence: 96%

A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the Mini-Muscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice

et al. 2013

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Replicated artificial selection for high levels of voluntary wheel running in an outbred strain of mice favored an autosomal recessive allele whose primary phenotypic effect is a 50% reduction in hind-limb muscle mass. Within the High Runner (HR) lines of mice, the numerous pleiotropic effects (e.g., larger hearts, reduced total body mass and fat mass, longer hind-limb bones) of this hypothesized adaptive allele include functional characteristics that facilitate high levels of voluntary wheel running (e.g., doubling of mass-specific muscle aerobic capacity, increased fatigue resistance of isolated muscles, longer hind-limb bones). Previously, we created a backcross population suitable for mapping the responsible locus. We phenotypically characterized the population and mapped the Minimsc locus to a 2.6-Mb interval on MMU11, a region containing 100 known or predicted genes. Here, we present a novel strategy to identify the genetic variant causing the mini-muscle phenotype. Using high-density genotyping and whole-genome sequencing of key backcross individuals and HR mice with and without the mini-muscle mutation, from both recent and historical generations of the HR lines, we show that a SNP representing a C-to-T transition located in a 709-bp intron between exons 11 and 12 of the Myosin heavy polypeptide 4 (Myh4) skeletal muscle gene (position 67,244,850 on MMU11; assembly, December 2011, GRCm38/mm10; ENSMUSG00000057003) is responsible for the mini-muscle phenotype, Myh4 Minimsc . Using next-generation sequencing, our approach can be extended to identify causative mutations arising in mouse inbred lines and thus offers a great avenue to overcome one of the most challenging steps in quantitative genetics.

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Section: Discussionmentioning

confidence: 96%

A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the Mini-Muscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice

et al. 2013

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“…Adult mice were fed an obesity-inducing diet (Table S2) that mimics the Western diet linked to risk of cardiovascular diseases in humans (13)(14)(15), and immediately started on a therapeutic regimen of ShK-186 or vehicle. ShK-186's durable pharmacological activity in rodents and nonhuman primates (16) allowed us to administer the peptide every other day by s.c. injection.…”

Section: Resultsmentioning

confidence: 99%

“…In this model, mice fed an obesity-inducing diet rich in both fat and fructose (Tables S2 and S3) gain significant weight and adiposity, and develop insulin resistance within 6-8 wk (12)(13)(14)(15). As a Kv1.3 blocker we chose ShK-186 because of its picomolar potency (IC 50 69 pM), >100-fold selectivity over closely related channels, weak immunogenicity, and excellent safety profile in rodents and nonhuman primates (16)(17)(18)(19)(20)(21).…”

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confidence: 99%

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

Upadhyay¹,

Eckel‐Mahan²,

Mirbolooki³

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Obesity is an epidemic, calling for innovative and reliable pharmacological strategies. Here, we show that ShK-186, a selective and potent blocker of the voltage-gated Kv1.3 channel, counteracts the negative effects of increased caloric intake in mice fed a diet rich in fat and fructose. ShK-186 reduced weight gain, adiposity, and fatty liver; decreased blood levels of cholesterol, sugar, HbA1c, insulin, and leptin; and enhanced peripheral insulin sensitivity. These changes mimic the effects of Kv1.3 gene deletion. ShK-186 did not alter weight gain in mice on a chow diet, suggesting that the obesityinducing diet enhances sensitivity to Kv1.3 blockade. Several mechanisms may contribute to the therapeutic benefits of ShK-186. ShK-186 therapy activated brown adipose tissue as evidenced by a doubling of glucose uptake, and increased β-oxidation of fatty acids, glycolysis, fatty acid synthesis, and uncoupling protein 1 expression. Activation of brown adipose tissue manifested as augmented oxygen consumption and energy expenditure, with no change in caloric intake, locomotor activity, or thyroid hormone levels. The obesity diet induced Kv1.3 expression in the liver, and ShK-186 caused profound alterations in energy and lipid metabolism in the liver. This action on the liver may underlie the differential effectiveness of ShK-186 in mice fed a chow vs. an obesity diet. Our results highlight the potential use of Kv1.3 blockers for the treatment of obesity and insulin resistance.

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“…in hunger, satiety or dietary adherence (Schoeller, 2009). Moreover, alterations in specific dietary components can have effects that go far beyond their effects on energy intake [Jebb (Jebb, 2007) and references therein] (Meek et al, 2010). Hence, prospective use of the energy balance equation can be a risky proposition with respect to bringing about reductions in human body fat (Schoeller, 2009).…”

Section: Dee and Its Componentsmentioning

confidence: 99%

The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives

Garland

Schutz

Chappell

et al. 2011

Journal of Experimental Biology

381

434

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Summary Mammals expend energy in many ways, including basic cellular maintenance and repair, digestion, thermoregulation, locomotion, growth and reproduction. These processes can vary tremendously among species and individuals, potentially leading to large variation in daily energy expenditure (DEE). Locomotor energy costs can be substantial for large-bodied species and those with high-activity lifestyles. For humans in industrialized societies, locomotion necessary for daily activities is often relatively low, so it has been presumed that activity energy expenditure and DEE are lower than in our ancestors. Whether this is true and has contributed to a rise in obesity is controversial. In humans, much attention has centered on spontaneous physical activity (SPA) or non-exercise activity thermogenesis (NEAT), the latter sometimes defined so broadly as to include all energy expended due to activity, exclusive of volitional exercise. Given that most people in Western societies engage in little voluntary exercise, increasing NEAT may be an effective way to maintain DEE and combat overweight and obesity. One way to promote NEAT is to decrease the amount of time spent on sedentary behaviours (e.g. watching television). The effects of voluntary exercise on other components of physical activity are highly variable in humans, partly as a function of age, and have rarely been studied in rodents. However, most rodent studies indicate that food consumption increases in the presence of wheels; therefore, other aspects of physical activity are not reduced enough to compensate for the energetic cost of wheel running. Most rodent studies also show negative effects of wheel access on body fat, especially in males. Sedentary behaviours per se have not been studied in rodents in relation to obesity. Several lines of evidence demonstrate the important role of dopamine, in addition to other neural signaling networks (e.g. the endocannabinoid system), in the control of voluntary exercise. A largely separate literature points to a key role for orexins in SPA and NEAT. Brain reward centers are involved in both types of physical activities and eating behaviours, likely leading to complex interactions. Moreover, voluntary exercise and, possibly, eating can be addictive. A growing body of research considers the relationships between personality traits and physical activity, appetite, obesity and other aspects of physical and mental health. Future studies should explore the neurobiology, endocrinology and genetics of physical activity and sedentary behaviour by examining key brain areas, neurotransmitters and hormones involved in motivation, reward and/or the regulation of energy balance.

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Western diet increases wheel running in mice selectively bred for high voluntary wheel running

Cited by 59 publications

References 59 publications

A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the Mini-Muscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice

A Novel Intronic Single Nucleotide Polymorphism in the Myosin heavy polypeptide 4 Gene Is Responsible for the Mini-Muscle Phenotype Characterized by Major Reduction in Hind-Limb Muscle Mass in Mice

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

The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives

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