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Anti-obesity effects of α-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase

Nature Medicine volume 10, pages 727–733 (2004)Cite this article

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Abstract

AMP-activated protein kinase (AMPK) functions as a fuel sensor in the cell and is activated when cellular energy is depleted. Here we report that α-lipoic acid (α-LA), a cofactor of mitochondrial enzymes, decreases hypothalamic AMPK activity and causes profound weight loss in rodents by reducing food intake and enhancing energy expenditure. Activation of hypothalamic AMPK reverses the effects of α-LA on food intake and energy expenditure. Intracerebroventricular (i.c.v.) administration of glucose decreases hypothalamic AMPK activity, whereas inhibition of intracellular glucose utilization through the administration of 2-deoxyglucose increases hypothalamic AMPK activity and food intake. The 2-deoxyglucose-induced hyperphagia is reversed by inhibiting hypothalamic AMPK. Our findings indicate that hypothalamic AMPK is important in the central regulation of food intake and energy expenditure and that α-LA exerts anti-obesity effects by suppressing hypothalamic AMPK activity.

NOTE: In the version of this article initially published online, the name of an author was misspelled. The name of the twelfth author should be “Benoit Viollet”. This error has been corrected for the HTML and print versions of the article

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Figure 1: α-LA causes weight loss and anorexia.
Figure 2: α-LA increases energy expenditure and expression of Ucp1 in BAT.
Figure 3: Anti-obesity effect of α-LA is not dependent on leptin.
Figure 4: α-LA suppresses hypothalamic AMPK activity.
Figure 5: AMPK activation reverses the effect of α-LA on food intake and energy expenditure.
Figure 6: Hypothalamic AMPK activity is dependent on energy status.

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  • 20 June 2004

    Corrected the name to Benoit Viollet

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Acknowledgements

We thank M. Schwartz for critically reading the manuscript and E. Souil for technical support. This study was supported by a National Research Laboratory grant from the Ministry of Science and Technology (M1-0104-00-0103) and grants from the Ministry of Health & Welfare (03-PJ1-PG1-CH05-0005) of the Republic of Korea, the Korea Research Council of Fundamental Science and Technology, and the Asan Institute for Life Sciences (2004-006).

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Authors and Affiliations

  1. Department of Internal Medicine, University of Ulsan College of Medicine, 138-736 Poongnap-dong, Songpa-ku, Seoul, 138-736, Korea

    Min-Seon Kim, Joong-Yeol Park, Il-Seong Namgoong & Ki-Up Lee

  2. Asan Institute for Life Sciences, University of Ulsan College of Medicine, 138-736 Poongnap-dong, Songpa-ku, Seoul, 138-736, Korea

    Cherl Namkoong, Pil-Geum Jang, Je-Won Ryu, Hai-Sun Song & Ji-Young Yun

  3. Department of Molecular Biology, Kyunghee University College of Medicine, 1 Hoegi-dong Tongdaemun-gu, Seoul, 130-701, Korea

    Joohun Ha

  4. Department of Anatomy, College of Medicine, Inha University, 7-241 Shinheung-dong, Choong-ku, Incheon, 400-103, Korea

    In-Sun Park

  5. Department of Internal Medicine, Keimyung University School of Medicine, 194 Dongsan-dong, Taegu, 700-310, Korea

    In-Kyu Lee

  6. Department of Genetics, Development and Molecular Pathology, Institut Cochin, INSERM, CNRS, Rene Descartes University, 24 rue du Faubourg Saint-Jacques, Paris, 75014, France

    Benoit Viollet

  7. Department of Physiology and Biophysics, University of Southern California Keck School of Medicine, 1333 San Pablo St. MMR626, Los Angeles, 90089, CA, USA

    Jang Hyun Youn

  8. Department of Internal Medicine, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-ku, Seoul, 110-744, Korea

    Hong-Kyu Lee

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Correspondence to Ki-Up Lee.

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Competing interests

The authors have submitted an application to the Korean patent office (no. 2000-31394), entitled “Agent increasing energy expenditure of the cell,” covering the use of α-lipoic acid as an anti-obesity agent.

Supplementary information

Supplementary Fig. 1

Anti-obesity effect of a-LA in genetically obese OLETF rats. (PDF 265 kb)

Supplementary Fig. 2

α-LA decreases fatty acid oxidation. (PDF 10 kb)

Supplementary Table 1 (PDF 19 kb)

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Kim, MS., Park, JY., Namkoong, C. et al. Anti-obesity effects of α-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nat Med 10, 727–733 (2004). https://doi.org/10.1038/nm1061

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