Transgenic Mouse Models Resistant to Diet-Induced Metabolic Disease: Is Energy Balance the Key?: Fig. 1.

Gilliam, Laura; Neufer, P. Darrell

doi:10.1124/jpet.112.192146

Cited by 8 publications

(6 citation statements)

References 69 publications

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“…For example, the POLG mutator mice exhibit significant losses in oxidative capacity related to the loss of a mitochondrial DNA proofreading enzyme, but remained protected from the deleterious effects of an HFD because of higher glycolytic capacities (22). A recent review of the literature found several examples of mouse models that demonstrated metabolic protection from an HFD (23), with many of the mouse models that demonstrated metabolic protection exhibiting decreases in mitochondrial respiration. Altogether, this suggests that, temporarily, an animal can adapt to exposure to nutrient overload by altering the metabolic (i.e., glycolytic) phenotype of the skeletal muscle tissue.…”

Section: Discussionmentioning

confidence: 99%

Induced Cre‐mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high‐fat diet

et al. 2018

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The breast cancer type 1 susceptibility protein (Brca1) is a regulator of DNA repair in mammary gland cells; however, recent cell culture evidence suggests that Brca1 influences other processes, including those in nonmammary cells. In this study, we sought to determine whether Brca1 is necessary for metabolic regulation of skeletal muscle using a novel in vivo mouse model. We developed an inducible skeletal muscle-specific Brca1knockout (BRCA1KO) model to test whether Brca1 expression is necessary for maintenance of metabolic function of skeletal muscle when exposed to a high-fat diet (HFD). Our data demonstrated that deletion of Brca1 prevented HFD-induced alterations in glucose and insulin tolerance. Irrespective of diet, BRCA1KO mice exhibited significantly lower ADP-stimulated complex I mitochondrial respiration rates compared to age-matched wild-type (WT) mice. The data show that Brca1 has the ability to localize to the mitochondria in skeletal muscle and that BRCA1KO mice exhibit higher whole-body CO production, respiratory exchange ratio, and energy expenditure, compared with the WT mice. Our results demonstrate that loss of Brca1 in skeletal muscle leads to dysregulated metabolic function, characterized by decreased mitochondrial respiration. Thus, any condition that results in loss of Brca1 function could induce metabolic imbalance in skeletal muscle.-Jackson, K. C., Tarpey, M. D., Valencia, A. P., Iñigo, M. R., Pratt, S. J., Patteson, D. J., McClung, J. M., Lovering, R. M., Thomson, D. M., Spangenburg, E. E. Induced Cre-mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high-fat diet.

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Section: Discussionmentioning

confidence: 99%

Induced Cre‐mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high‐fat diet

et al. 2018

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“…Also requiring study is why some obese people remain insulin sensitive, whereas the majority of them are insulin resistant. In addition to the possibilities already discussed, such factors as alterations in capillary density and permeability (136,137), differences in collagen VI deposition (53,138,139), the release of LPS from bacteria by the gut microbiome (140)(141)(142), alterations of lipid droplet proteins such as FSP27 (CIDEC) that regulate the rates of lipid deposition and lipolysis in adipose tissue (19,143), and events that cause an imbalance between nutrient load and mitochondrial function (144), need to be considered. With respect to the microbiome, AMPK activity is significantly increased in tissues of germfree mice (145) and in mice treated with antibiotics (146), suggesting that AMPK suppression by factors released by bacteria of the gastrointestinal tract or other sites may be a normal occurrence.…”

Section: Figurementioning

confidence: 99%

AMPK, insulin resistance, and the metabolic syndrome

Ruderman¹,

Carling²,

Prentki³

et al. 2013

J. Clin. Invest.

708

531

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IntroductionThe fuel-sensing enzyme AMP-activated protein kinase (AMPK) was first described as an enzyme activated by changes in the AMP/ATP ratio that could both increase cellular ATP generation (e.g., fatty acid oxidation) and diminish ATP use for less critical processes (e.g., fatty acid, triglyceride, and protein synthesis) (1). In addition to glucose transport, lipid and protein synthesis, and fuel metabolism, AMPK regulates a wide array of other physiological events, including cellular growth and proliferation, mitochondrial function and biogenesis, and factors that have been linked to insulin resistance (IR), including inflammation, oxidative and ER stress, and autophagy ( Figure 1A). Furthermore, AMPK does so by phosphorylating both key enzymes and transcriptional activators and coactivators.Here, we examine 2 hypotheses suggested by more recent studies: (a) dysregulation of AMPK plays an important role in the pathogenesis of IR and metabolic syndrome-associated diseases in humans and experimental animals; and (b) strategies that activate AMPK can be harnessed for the prevention and treatment of these abnormalities. These hypotheses emanated from associations between the metabolic syndrome and some downstream targets of AMPK, such as glucose transport and lipogenesis (2-8). In addition, exercise (9) and electrically induced contractions (10) were shown to activate AMPK. These observations, coupled with epidemiological evidence that diseases associated with the metabolic syndrome (e.g., type 2 diabetes, hypertension, atherosclerotic cardiovascular disease [ASCVD], and even certain cancers) are less prevalent in physically active people (11-13) and the demonstration that regular exercise improves whole-body insulin action (11, 12), suggest a central role for AMPK in regulating insulin sensitivity. Such studies also raise the possibility that pharmacological AMPK activators as well as exercise could be used for ameliorating IR in type 2 diabetes (4,8).In model systems, sustained decreases in AMPK activity accompany IR, whereas AMPK activation increases insulin sensitivity (5, 6, 13). In addition, decreases in AMPK activity accompanying IR were described in adipose tissue of humans with Cushing's syndrome, an effect attributable to high levels of glucocorticoids (14), and in a subgroup of very obese patients undergoing bariatric surgery who were insulin resistant (15, 16). The latter comprise approximately 75% of bariatric surgery patients and show a greater predisposition to metabolic syndrome-associated diseases than do the remaining 25% of such patients who are equally obese, but less hyperinsulinemic and more insulin sensitive (17-19). Insulin resistance in physiology and diseaseStudies with a perfused rat hindquarter preparation demonstrated that insulin-stimulated glucose uptake in skeletal muscle is reduced in fed versus fasted rats (20) and in sedentary versus recently exercised rats (21), suggesting that the fed and sedentary rats are essentially more insulin resistant. Such IR is physiological, rat...

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“…When intentionally overfed, participants failed to compensate by raising voluntary activity (11). This failure of a “push mechanism” by energy intake also applies to cellular bioenergetics, because energy expenditure in all cells is not directly coupled to energy supply but rather is determined by the rate of energy turnover (pull mechanism) (53). Hence, increased energy turnover was identified as a common underlying protective mechanism in various genetic models resistant to diet‐induced metabolic disease (53‐56).…”

Section: Impact Of Energy Turnover On Energy Partitioning and Metabolic Healthmentioning

confidence: 99%

Impact of Energy Turnover on the Regulation of Energy and Macronutrient Balance

Bosy‐Westphal

Hägele

Müller

2021

Obesity

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Energy turnover, defined as the average daily total metabolic rate, can be normalized for basal metabolic rate in order to compare physical activity level between individuals, whereas normalization of energy turnover for energy intake (energy flux) allows investigation of its impact on regulation of energy partitioning independent of energy balance. Appetite sensations better correspond to energy requirements at a high compared with a low energy turnover. Adaptation of energy intake to habitual energy turnover may, however, contribute to the risk of weight gain associated with accelerated growth, pregnancy, detraining in athletes, or after weight loss in people with obesity. The dose–response relationship between energy turnover and energy intake as well as the metabolic effects of energy turnover varies with the habitual level of physical activity and the etiology of energy turnover (e.g., cold‐induced thermogenesis, growth, or lactation; aerobic vs. anaerobic exercise). Whether a high energy turnover due to physical activity or exercise may compensate for adverse effects of overfeeding or an unhealthy diet needs to be further investigated using the concept of energy flux. In summary, the beneficial effects of a high energy turnover on regulation of energy and macronutrient balance facilitate the prevention and treatment of obesity and associated metabolic risk.

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Transgenic Mouse Models Resistant to Diet-Induced Metabolic Disease: Is Energy Balance the Key?: Fig. 1.

Cited by 8 publications

References 69 publications

Induced Cre‐mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high‐fat diet

Induced Cre‐mediated knockdown of Brca1 in skeletal muscle reduces mitochondrial respiration and prevents glucose intolerance in adult mice on a high‐fat diet

AMPK, insulin resistance, and the metabolic syndrome

Impact of Energy Turnover on the Regulation of Energy and Macronutrient Balance

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