C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity

Thupari, Jagan N.; Landree, Leslie E.; Ronnett, Gabriele V.; Kuhajda, Francis P.

doi:10.1073/pnas.132128899

Cited by 243 publications

(272 citation statements)

References 18 publications

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“…Fatty acid oxidation Following incubation, 14 CO 2 was measured according to the method of Thupari et al [35] with some modifications. Adipocytes were preincubated for 30 min with 1. palmitate) bound to albumin, and the cells were incubated at 37°C for 2 h. After incubation, the plate was clamped and sealed, and perchloric acid was injected into the medium through the holes in the lid, driving CO 2 through the tunnel into an adjacent well, where it was trapped in 1 mol/l NaOH.…”

Section: Methodsmentioning

confidence: 99%

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

et al. 2007

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Aims/hypothesis The aim of the study was to address the importance of mitochondrial function in insulin resistance and type 2 diabetes, and also to identify effective agents for ameliorating insulin resistance in type 2 diabetes. We examined the effect of two mitochondrial nutrients, R-α-lipoic acid (LA) and acetyl-L-carnitine (ALC), as well as their combined effect, on mitochondrial biogenesis in 3T3-L1 adipocytes. Methods Mitochondrial mass and oxygen consumption were determined in 3T3-L1 adipocytes cultured in the presence of LA and/or ALC for 24 h. Mitochondrial DNA and mRNA from peroxisome proliferator-activated receptor gamma and alpha (Pparg and Ppara) and carnitine palmitoyl transferase 1a (Cpt1a), as well as several transcription factors involved in mitochondrial biogenesis, were evaluated by real-time PCR or electrophoretic mobility shift (EMSA) assay. Mitochondrial complexes proteins were measured by western blot and fatty acid oxidation was measured by quantifying CO 2 production from [1-14 C] palmitate. Results Treatments with the combination of LA and ALC at concentrations of 0.1, 1 and 10 μmol/l for 24 h significantly increased mitochondrial mass, expression of mitochondrial DNA, mitochondrial complexes, oxygen consumption and fatty acid oxidation in 3T3L1 adipocytes. These changes were accompanied by an increase in expression of Pparg, Ppara and Cpt1a mRNA, as well as increased expression of peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1 alpha (Ppargc1a), mitochondrial transcription factor A (Tfam) and nuclear respiratory factors 1 and 2 (Nrf1 and Nrf2). However, the treatments with LA or ALC alone at the same concentrations showed little effect on mitochondrial function and biogenesis. Conclusions/interpretation We conclude that the combination of LA and ALC may act as PPARG/A dual ligands to complementarily promote mitochondrial synthesis and adipocyte metabolism.

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Section: Methodsmentioning

confidence: 99%

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

et al. 2007

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“…C75 is a synthetic inhibitor of fatty acid synthase (FAS) [1] and has been proposed as an anti-obesity agent since its administration decreases food intake and body weight in rodents [2][3][4][5]. C75 can alter the metabolism of neurons in the hypothalamus, where an increase in the level of malonyl-CoA due to FAS inhibition serves as a secondary messenger of nutrient status, thereby mediating the suppression of food intake [6,7].…”

Section: Introductionmentioning

confidence: 99%

C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight

Mera

Bentebibel

López-Viñas

et al. 2009

Biochemical Pharmacology

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runathan, et al.. C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight. Biochemical Pharmacology, Elsevier, 2009, 77 (6) 20-11-2008 Please cite this article as: Mera P, Bentebibel A, López-Viñas E, Cordente AG, Gurunathan C, Sebastián D, Vázquez I, Herrero L, Ariza X, Gómez-Puertas P, Asins G, Serra D, García J, Hegardt FG, C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight, Biochemical Pharmacology (2008Pharmacology ( ), doi:10.1016Pharmacology ( /j.bcp.2008 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 3 ABSTRACT Central nervous system administration of C75 produces hypophagia and weight loss in rodents identifying C75 as a potential drug against obesity and type 2 diabetes.However, the mechanism underlying this effect is unknown. Here we show that C75-CoA is generated chemically, in vitro and in vivo from C75 and that it is a potent inhibitor of carnitine palmitoyltranferase 1 (CPT1), the rate-limiting step of fatty acid oxidation. Three-D docking and kinetic analysis support the inhibitory effect of C75-CoA on CPT1. Central nervous system administration of C75 in rats led to C75-CoA production, inhibition of CPT1 and lower body weight and food intake. Our results suggest that inhibition of CPT1, and thus increased availability of fatty acids in the hypothalamus, contribute to the pharmacological mechanism of C75 to decrease food intake.

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“…In fact, C75 actions on metabolism in a variety of tissues and cell types have shown complete concordance. [7][8][9][10]26 However, the consequences of these responses are specific to tissue and cell type. The hypothalamus is uniquely poised to sense energy status, and to respond to metabolic challenges to manage whole-body energy balance, but cortical and cerebellar neurons are not.…”

Section: C75 and Ampk In Other Brain Areasmentioning

confidence: 99%

“…[4][5][6] Our interest in hypothalamic AMPK grew from our work with C75, a synthetic molecule that inhibits fatty acid synthase (FAS) 7 and stimulates carnitine palmitoyltransferase-1 (CPT-1) and beta-oxidation of fatty acids. [8][9][10] Fatty acid metabolic pathways are poised at a crossroads of energy deficit and energy surplus, with the potential to either use or make the high-energy molecule ATP. We have shown that C75 increases cellular ATP, and decreases the phosphorylation status and activity of AMPK.…”

Section: Introductionmentioning

confidence: 99%

“…7 C75 reduces fatty acid synthesis in every tissue and cell type tested so far (liver, white fat, bone, carcinoma and neuron). [7][8][9][10]26 C75 also competes with malonyl-CoA, thus increasing CPT-1 activity. [8][9][10] C75 potently increases fatty acid oxidation and ATP levels in vitro 8,10,26 by increasing CPT-1 activity (CPT-1s), even in the presence of elevated, inhibitory concentrations of malonyl-CoA.…”

Section: Introductionmentioning

confidence: 99%

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AMP-activated protein kinase in the brain

Ronnett

2008

Int J Obes

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Since its discovery as an important regulator of fuel utilization in the periphery, AMP-activated protein kinase (AMPK) has become a contender for many important cell-intrinsic and organismal roles regarding energy balance in the central nervous system. The challenge will be to delineate the mechanisms by which neuronal AMPK can respond to cellular energy requirements as well as whole body energy demands. Thus, under physiological conditions in the brain, hypothalamic AMPK responds to changes in energy balance/food intake, whereas under pathological conditions, AMPK responds globally in the brain to energy challenge. Modulation of fatty acid metabolism affects energy balance in a context-specific manner and may provide an insight into other mechanisms for selective activation or inhibition of AMPK activity for therapeutic applications.

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C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity

Cited by 243 publications

References 18 publications

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

R-α-Lipoic acid and acetyl-l-carnitine complementarily promote mitochondrial biogenesis in murine 3T3-L1 adipocytes

C75 is converted to C75-CoA in the hypothalamus, where it inhibits carnitine palmitoyltransferase 1 and decreases food intake and body weight

AMP-activated protein kinase in the brain

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