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
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
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).
Friedman, J.M. Obesity in the new millennium. Nature 404, 632–634 (2000).
Flier, J.S. Obesity wars: molecular progress confronts an expanding epidemic. Cell 116, 337–350 (2004).
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).
Halaas, J.L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).
Loftus, T.M. et al. Reduced food intake and body weight in mice treated with fatty acid synthase inhibitors. Science 288, 2379–2381 (2000).
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).
Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).
Lam, T.K. et al. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat. Med. 11, 320–327 (2005).
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).
Pocai, A. et al. Hypothalamic KATP channels control hepatic glucose production. Nature 434, 1026–1031 (2005).
Ruderman, N. & Prentki, M. AMP kinase and malonyl-CoA: targets for therapy of the metabolic syndrome. Nat. Rev. Drug Discov. 3, 340–351 (2004).
An, J. et al. Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nat. Med. 10, 268–274 (2004).
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).
Lam, T.K., Schwartz, G.J. & Rossetti, L. Hypothalamic sensing of fatty acids. Nat. Neurosci. 8, 579–584 (2005).
Schwartz, M.W. & Porte, D. Jr. Diabetes, obesity, and the brain. Science 307, 375–379 (2005).
Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994).
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).
Lee, G.H. et al. Abnormal splicing of the leptin receptor in diabetic mice. Nature 379, 632–635 (1996).
Bruning, J.C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).
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).
Montague, C.T. et al. Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387, 903–908 (1997).
Clement, K. et al. A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392, 398–401 (1998).
McGarry, J.D. Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes. Diabetes 51, 7–18 (2002).
Obici, S. et al. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271–275 (2002).
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).
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).
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).
Barzilai, N. et al. Leptin selectively decreases visceral adiposity and enhances insulin action. J. Clin. Invest. 100, 3105–3110 (1997).
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).
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).
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
Corresponding author
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
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn1626
This article is cited by
-
Neuronal control of peripheral nutrient partitioning
Diabetologia (2020)
-
Impact of obesity on taste receptor expression in extra-oral tissues: emphasis on hypothalamus and brainstem
Scientific Reports (2016)
-
Neurotrophic factor control of satiety and body weight
Nature Reviews Neuroscience (2016)
-
A fatty acid-dependent hypothalamic–DVC neurocircuitry that regulates hepatic secretion of triglyceride-rich lipoproteins
Nature Communications (2015)