Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Molecular disruption of hypothalamic nutrient sensing induces obesity

Abstract

The sensing of circulating nutrients within the mediobasal hypothalamus may be critical for energy homeostasis. To induce a sustained impairment in hypothalamic nutrient sensing, adeno-associated viruses (AAV) expressing malonyl–coenzyme A decarboxylase (MCD; an enzyme involved in the degradation of malonyl coenzyme A) were injected bilaterally into the mediobasal hypothalamus of rats. MCD overexpression led to decreased abundance of long-chain fatty acyl–coenzyme A in the mediobasal hypothalamus and blunted the hypothalamic responses to increased lipid availability. The enhanced expression of MCD within this hypothalamic region induced a rapid increase in food intake and progressive weight gain. Obesity was sustained for at least 4 months and occurred despite increased plasma concentrations of leptin and insulin. These findings indicate that nutritional modulation of the hypothalamic abundance of malonyl–coenzyme A is required to restrain food intake and that a primary impairment in this central nutrient-sensing pathway is sufficient to disrupt energy homeostasis and induce obesity.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Overexpression of MCD in HEK293 cells.
Figure 2: Hypothalamic (MBH) overexpression of malonyl-CoA decarboxylase (MCD).
Figure 3: MCD overexpression in the MBH disrupts central lipid sensing and liver glucose homeostasis.
Figure 4: MCD overexpression in the MBH disrupts energy homeostasis.
Figure 5: Effect of MCD-AAV on body composition and energy metabolism.
Figure 6: Altered regulation of food intake in rats with MCD overexpression in the MBH.
Figure 7: Nutritional regulation of hypothalamic LCFA-CoA levels.

Similar content being viewed by others

References

  1. Schwartz, M.W., Woods, S.C., Porte, D. Jr., Seeley, R.J. & Baskin, D.G. Central nervous system control of food intake. Nature 404, 661–671 (2000).

    Article  CAS  Google Scholar 

  2. Friedman, J.M. Obesity in the new millennium. Nature 404, 632–634 (2000).

    Article  CAS  Google Scholar 

  3. Flier, J.S. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350 (2004).

    Article  CAS  Google Scholar 

  4. Woods, S.C., Lotter, E.C., McKay, L.D. & Porte, D. Jr. Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature 282, 503–505 (1979).

    Article  CAS  Google Scholar 

  5. Halaas, J.L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).

    Article  CAS  Google Scholar 

  6. Loftus, T.M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000).

    Article  CAS  Google Scholar 

  7. Obici, S., Feng, Z., Arduini, A., Conti, R. & Rossetti, L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat. Med. 9, 756–761 (2003).

    Article  CAS  Google Scholar 

  8. Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).

    Article  CAS  Google Scholar 

  9. Lam, T.K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat. Med. 11, 320–327 (2005).

    Article  CAS  Google Scholar 

  10. Obici, S., Zhang, B.B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376–1382 (2002).

    Article  CAS  Google Scholar 

  11. Pocai, A. et al. Hypothalamic KATP channels control hepatic glucose production. Nature 434, 1026–1031 (2005).

    Article  CAS  Google Scholar 

  12. Ruderman, N. & Prentki, M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat. Rev. Drug Discov. 3, 340–351 (2004).

    Article  CAS  Google Scholar 

  13. An, J. et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat. Med. 10, 268–274 (2004).

    Article  CAS  Google Scholar 

  14. Hu, Z., Cha, S.H., Chohnan, S. & Lane, M.D. Hypothalamic malonyl-CoA as a mediator of feeding behavior. Proc. Natl. Acad. Sci. USA 100, 12624–12629 (2003).

    Article  CAS  Google Scholar 

  15. Lam, T.K., Schwartz, G.J. & Rossetti, L. Hypothalamic sensing of fatty acids. Nat. Neurosci. 8, 579–584 (2005).

    Article  CAS  Google Scholar 

  16. Schwartz, M.W. & Porte, D. Jr. Diabetes, obesity, and the brain. Science 307, 375–379 (2005).

    Article  CAS  Google Scholar 

  17. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).

    Article  CAS  Google Scholar 

  18. Chua, S.C. Jr. et al. Phenotypes of mouse diabetes and rat fatty due to mutations in the OB (leptin) receptor. Science 271, 994–996 (1996).

    Article  CAS  Google Scholar 

  19. Lee, G.H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).

    Article  CAS  Google Scholar 

  20. Bruning, J.C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).

    Article  CAS  Google Scholar 

  21. Obici, S., Feng, Z., Karkanias, G., Baskin, D.G. & Rossetti, L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat. Neurosci. 5, 566–572 (2002).

    Article  CAS  Google Scholar 

  22. Montague, C.T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).

    Article  CAS  Google Scholar 

  23. Clement, K. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401 (1998).

    Article  CAS  Google Scholar 

  24. McGarry, J.D. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51, 7–18 (2002).

    Article  CAS  Google Scholar 

  25. Obici, S. et al. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271–275 (2002).

    Article  CAS  Google Scholar 

  26. Abu-Elheiga, L., Matzuk, M.M., Abo-Hashema, K.A. & Wakil, S.J. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 291, 2613–2616 (2001).

    Article  CAS  Google Scholar 

  27. Rossetti, L., Shulman, G.I., Zawalich, W. & DeFronzo, R.A. Effect of chronic hyperglycemia on in vivo insulin secretion in partially pancreatectomized rats. J. Clin. Invest. 80, 1037–1044 (1987).

    Article  CAS  Google Scholar 

  28. Rossetti, L. et al. Mechanism by which hyperglycemia inhibits hepatic glucose production in conscious rats. Implications for the pathophysiology of fasting hyperglycemia in diabetes. J. Clin. Invest. 92, 1126–1134 (1993).

    Article  CAS  Google Scholar 

  29. Barzilai, N. et al. Leptin selectively decreases visceral adiposity and enhances insulin action. J. Clin. Invest. 100, 3105–3110 (1997).

    Article  CAS  Google Scholar 

  30. McGarry, J.D., Stark, M.J. & Foster, D.W. Hepatic malonyl-CoA levels of fed, fasted and diabetic rats as measured using a simple radioisotopic assay. J. Biol. Chem. 253, 8291–8293 (1978).

    CAS  PubMed  Google Scholar 

  31. Hosokawa, Y., Shimomura, Y., Harris, R.A. & Ozawa, T. Determination of short-chain acyl-coenzyme A esters by high-performance liquid chromatography. Anal. Biochem. 153, 45–49 (1986).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We wish to thank C. Baveghems, B. Liu, H. Zhang and S. Gaweda for expert technical assistance. This work was supported by the US National Institutes of Health, the American Diabetes Association and the Skirball Foundation.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Luciano Rossetti.

Ethics declarations

Competing interests

Albert Einstein College of Medicine has a patent application on the use of inhibitors of carnitine palmityltransferases for therapeutic purposes.

Supplementary information

Supplementary Fig. 1

Construction and validation of the pMCD-AAV. (PDF 83 kb)

Supplementary Fig. 2

Role of hypothalamic malonyl-CoA in fasted and fed state. (PDF 179 kb)

Supplementary Table 1

Characteristics of the two week pair-fed GFP-AAV vs. MCD-AAV injected animals. (PDF 262 kb)

Supplementary Table 2

Characteristics of the two week pair-fed GFP-AAV vs. MCD-AAV injected animals during the pancreatic clamps. (PDF 272 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

He, W., Lam, T., Obici, S. et al. Molecular disruption of hypothalamic nutrient sensing induces obesity. Nat Neurosci 9, 227–233 (2006). https://doi.org/10.1038/nn1626

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1626

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing