Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with ‘exercise mimetics’

Carey, Andrew L.; Kingwell, Bronwyn A.

doi:10.1007/s00125-009-1420-x

Cited by 41 publications

(49 citation statements)

References 102 publications

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“…Basically, exercise mimetics would be expected to show the same effects as those gained with normal endurance exercise; namely, increased metabolism in the skeletal muscles as well as changes in their contractile properties. Since these adaptations, particularly in skeletal muscles, are very complex, many researchers deny the existence of 'exercise pills' that are able to exactly replicate exercise-induced physiological changes associated with gene regulation in cells, tissues, and organs in response to different types of exercise [117][118][119]. This attitude is supported by studies investigating AMPK and exercise effects.…”

Section: Discussionmentioning

confidence: 95%

Activation of AMPK and its Impact on Exercise Capacity

et al. 2015

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Activation of the adenosine monophosphate (AMP)-activated kinase (AMPK) contributes to beneficial effects such as improvement of the hyperglycemic state in diabetes as well as reduction of obesity and inflammatory processes. Furthermore, stimulation of AMPK activity has been associated with increased exercise capacity. A study published in 2008, directly before the Olympic Games in Beijing, showed that the AMPK activator AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide) increased the running capacity of mice without any training and thus, prompted the World Anti-Doping Agency (WADA) to include certain AMPK activators in the list of forbidden drugs. This raises the question as to whether all AMPK activators should be considered for registration or whether the increase in exercise performance is only associated with specific AMPK-activating substances. In this review, we intend to shed light on currently published AMPK-activating drugs, their working mechanisms, and their impact on body fitness.

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Section: Discussionmentioning

confidence: 95%

Activation of AMPK and its Impact on Exercise Capacity

et al. 2015

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“…5 PGC-1a interacts with NRF-1 and stimulates the expression of Tfam, which regulates mitochondrial DNA replication, transcription, and oxidative phosphorylation. 20 PGC-1a also stimulates ERRa expression and regulates fatty acid oxidation and the expression of OXPHOS enzymes. 21 BPE increased the mRNA expression of PGC-1a and other mitochondrial transcription factors such as ERRa, NRF-1, and Tfam.…”

Section: Discussionmentioning

confidence: 99%

Standardized Boesenbergia pandurata Extract Stimulates Exercise Endurance Through Increasing Mitochondrial Biogenesis

Kim

et al. 2016

Journal of Medicinal Food

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In the present study, the effect of standardized Boesenbergia pandurata (Roxb.) Schltr. (fingerroot) ethanol extract on exercise endurance was investigated in L6 rat skeletal muscle cells and C57BL/6J mice. Standardized B. pandurata ethanol extract (BPE) increased mitochondrial mass and stimulated the mRNA expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α) in vitro. BPE also elevated the mRNA expression of key factors of mitochondrial biogenesis and function, which are activated by PGC-1α, such as estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam). In animal models, both normal and high-fat diet (HFD)-induced obese mice treated with BPE ran much longer than their respective controls. In addition, BPE increased the protein expressions of phosphorylated AMP-activated protein kinase (AMPK), sirtuin 1 (SIRT1), PGC-1α, and peroxisome proliferator-activated receptor delta (PPARδ), which are stimulated by exercise. These results indicate that B. pandurata could be a potential nutraceutical candidate for enhancing exercise endurance based on its mitochondrial biogenesis and exercise-mimicking effects.

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“…PGC-1α is an attractive target for such interventions because this protein is central to endurance exercise adaptation and by itself is sufficient to induce a trained phenotype along with an elevated metabolic capacity [3; 4; 5; 13]. Moreover, known experimental "exercise mimetics", including activators for AMPdependent protein kinase, at least in part act through PGC-1α [20]. Importantly however, when oxidative metabolism is promoted in excess, or when only individual oxidative pathways are increased without simultaneous up-regulation of subsequent steps, adverse effects on metabolic functions occur [14; 15].…”

Section: Discussionmentioning

confidence: 99%

Coordinated balancing of muscle oxidative metabolism through PGC-1α increases metabolic flexibility and preserves insulin sensitivity

Summermatter

Troxler

Santos

et al. 2011

Biochemical and Biophysical Research Communications

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Coordinated balancing of muscle oxidative metabolism through PGC-1α increases metabolic flexibility and preserves insulin sensitivity. Biochemical and biophysical research communications, Vol. 408, H. 1. S. 180-185.-1 - AbstractThe peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) enhances oxidative metabolism in skeletal muscle. Excessive lipid oxidation and electron transport chain activity can, however, lead to the accumulation of harmful metabolites and impair glucose homeostasis. Here, we investigated the effect of over-expression of PGC-1α on metabolic control and generation of insulin desensitizing agents in extensor digitorum longus (EDL), a muscle that exhibits low levels of PGC-1α in the untrained state and minimally relies on oxidative metabolism. We demonstrate that PGC-1α induces a strictly balanced substrate oxidation in EDL by concomitantly promoting the transcription of activators and inhibitors of lipid oxidation. Moreover, we show that PGC-1α enhances the potential to uncouple oxidative phosphorylation. Thereby, PGC-1α boosts elevated, yet tightly regulated oxidative metabolism devoid of side products that are detrimental for glucose homeostasis. Accordingly, PI3K activity, an early phase marker for insulin resistance, is preserved in EDL muscle. Our findings suggest that PGC-1α coordinately coactivates the simultaneous transcription of gene clusters implicated in the positive and negative regulation of oxidative metabolism and thereby increases metabolic flexibility. Thus, in mice fed a normal chow diet, over-expression of PGC-1α does not alter insulin sensitivity and the metabolic adaptations elicited by PGC-1α mimic the beneficial effects of endurance training on muscle metabolism in this context.

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Novel pharmacological approaches to combat obesity and insulin resistance: targeting skeletal muscle with ‘exercise mimetics’

Abstract: Chronic diseases arising from obesity will continue to escalate over coming decades. Current approaches to combating obesity include lifestyle measures, surgical interventions and drugs that target weight reduction or the metabolic consequences of obesity.

Cited by 41 publications

References 102 publications

Activation of AMPK and its Impact on Exercise Capacity

Activation of AMPK and its Impact on Exercise Capacity

Standardized Boesenbergia pandurata Extract Stimulates Exercise Endurance Through Increasing Mitochondrial Biogenesis

Coordinated balancing of muscle oxidative metabolism through PGC-1α increases metabolic flexibility and preserves insulin sensitivity

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