A comparison of sodium salicylate and 2:4-dinitrophenol as metabolic stimulants <i>in vitro</i>

Sproull, D. H.

doi:10.1042/bj0660527

Cited by 7 publications

(6 citation statements)

References 5 publications

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Section: Discussionsupporting

confidence: 60%

“…The compounds recently studied include a modified version of the classic protonophore, DNP (62), which is structurally similar to salicylate (53,67). These mitochondrial uncouplers result in an increase in energy expenditure similar to that obtained when treating with salsalate/salicylate (present work and previous studies [6,10,11,14,15,[52][53][54][55][56][57][58]) and also improve markers of NAFLD and T2D (62)(63)(64)(65)(66). Therefore, considering that mitochondrial uncouplers improve T2D and NAFLD, and increasing energy expenditure is a potent mechanism to improve T2D and NAFLD (62,63,(68)(69)(70), the present work, together with previous reports in mice and humans, is highly suggestive that salicylate-driven mitochondrial uncoupling is the primary mechanism of action explaining the improvement in T2D and NAFLD associated with salsalate treatment.…”

Section: Discussionmentioning

confidence: 70%

“…This is the first study to suggest that salicylate-driven mitochondrial uncoupling is the primary mechanism of action to explain the host of beneficial effects associated with salicylate (11,49,50) and salsalate (6-8,14,51,52). Data from the present study and previous investigations suggest that mitochondrial uncoupling resulting from the protonophoric properties of salicylate explains the consistently observed increases in energy expenditure in murine models and human subjects treated with salicylate-based compounds (6,10,11,14,15,(52)(53)(54)(55)(56)(57)(58).Classic studies from the 1950s observed that salicylate stimulates mitochondrial uncoupling (53,59), and previous work established that mitochondrial Δψm is reduced by 1.0 mmol/L salicylate (54). Moreover, proton conductance is increased with 1.0 mmol/L salicylate treatment (present data and ref.…”

mentioning

confidence: 62%

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Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

et al. 2016

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Salsalate is a prodrug of salicylate that lowers blood glucose in patients with type 2 diabetes (T2D) and reduces nonalcoholic fatty liver disease (NAFLD) in animal models; however, the mechanism mediating these effects is unclear. Salicylate directly activates AMPK via the β1 subunit, but whether salsalate requires AMPK-β1 to improve T2D and NAFLD has not been examined. Therefore, wild-type (WT) and AMPK-β1-knockout (AMPK-β1KO) mice were treated with a salsalate dose resulting in clinically relevant serum salicylate concentrations (~1 mmol/L). Salsalate treatment increased VO 2 , lowered fasting glucose, improved glucose tolerance, and led to an ~55% reduction in liver lipid content. These effects were observed in both WT and AMPK-β1KO mice. To explain these AMPK-independent effects, we found that salicylate increases oligomycin-insensitive respiration (state 4o) and directly increases mitochondrial proton Corresponding author: Gregory R. Steinberg, gsteinberg@mcmaster.ca. Duality of Interest. No potential conflicts of interest relevant to this article were reported.Author Contributions. B.K.S. and G.R.S. designed research studies, analyzed data, and wrote the manuscript. B.K.S., R.J.F., E.M.D., A.E.G., M.C.H., V.P.H., E.A.D., K.M., J.D.C., E.P.M., and C.G.R.P. conducted experiments and analyzed data. B.K.S., R.J.F., E.M.D., A.E.G., V.P.H., E.A.D., K.M., J.D.C., E.P.M., B.E.K., M.A.T., and G.R.S. edited the manuscript. G.R.S. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db16-0564/-/DC1. Diabetes. Author manuscript; available in PMC 2017 January 12.Published in final edited form as:Diabetes. 2016 November ; 65(11): 3352-3361. doi:10.2337/db16-0564. CIHR Author Manuscript CIHR Author Manuscript CIHR Author Manuscriptconductance at clinical concentrations. This uncoupling effect is tightly correlated with the suppression of de novo lipogenesis. Salicylate is also able to stimulate brown adipose tissue respiration independent of uncoupling protein 1. These data indicate that the primary mechanism by which salsalate improves glucose homeostasis and NAFLD is via salicylate-driven mitochondrial uncoupling.Nonalcoholic fatty liver disease (NAFLD) is considered an important contributing factor to the development of insulin resistance and type 2 diabetes (T2D) (1). Despite the rising prevalence of NAFLD and importance for the development of T2D, there are currently no pharmacological approaches for the treatment of this disease (2).Salsalate is a prodrug of salicylate and is hydrolyzed in the small intestine to produce two molecules of salicylate (3,4). The circulating concentration of salicylate in humans administered salsalate in T2D clinical trials is ~1 mmol/L (5-8). Salsalate has also been shown to improve symptoms of NAFLD (9) and nonalcoholic steatohepatitis in...

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 70%

mentioning

confidence: 62%

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Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

et al. 2016

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“…Another line of investigation is suggested by the observations that sodium salicylate stimulates the oxygen uptake of several tissues 20 and acts as a peripheralacting metabolic stimulant. 21 Wolff and his associates 22 present detailed data to demonstrate an "extrathyroidal hypermetabolic" effect of sodium salicylate.…”

mentioning

confidence: 99%

Salicylates and Carbohydrate Metabolism

Graef¹,

Gibbons²

1960

Diabetes

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“…In a small group (n = 6) of obese men with body mass indices of around 30, 2-week treatment with GW501516 induced a coordinate elevation of carnitine palmitoyl transferase 1b expression in skeletal muscle and increased whole body palmitate oxidation when measured as a 13 C-palmitate to 13 CO 2 conversion [57], clearly indicating a response similar to that seen in cell and animal models. [78]; dose response uncoupling of isolated mitochondria and rat thymocytes [37,39] Elevation of body temperature and oxygen consumption in rat and mice [79] Increased basal metabolism, oxygen consumption and temperature in patients [80] PPARγ (troglitazone) glucose uptake in L6 myotubes through AMPK activation [81];…”

Section: Fatty Acid Metabolism and Glucose Homeostasis: Pparsmentioning

confidence: 99%

Cell basedin vitroandex vivomodels in metabolic disease drug discovery: nice to have or critical path?

Hallén

Clapham

2009

Expert Opinion on Drug Discovery

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In terms of building target confidence, in vitro models are often the only mechanistic link to human systems early in a projects life. Many of the current targets in metabolic diseases in the early discovery phase are not yet clinically supported, let alone validated. In this respect, therefore, in vitro models warrant a place in the critical path in early discovery. In terms of any predictive role for decision-making today, this is much more difficult and is more likely pushed to a supporting role as part of a wider package. However, there is a rapid rate of advancement in this field and future developments hold much promise.

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A comparison of sodium salicylate and 2:4-dinitrophenol as metabolic stimulants in vitro

Cited by 7 publications

References 5 publications

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

Salsalate (Salicylate) Uncouples Mitochondria, Improves Glucose Homeostasis, and Reduces Liver Lipids Independent of AMPK-β1

Salicylates and Carbohydrate Metabolism

Cell basedin vitroandex vivomodels in metabolic disease drug discovery: nice to have or critical path?

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