Article | Published:

Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production

Nature Medicine volume 9, pages 756761 (2003) | Download Citation

Subjects

Abstract

The enzyme carnitine palmitoyltransferase-1 (CPT1) regulates long-chain fatty acid (LCFA) entry into mitochondria, where the LCFAs undergo β-oxidation. To investigate the mechanism(s) by which central metabolism of lipids can modulate energy balance, we selectively reduced lipid oxidation in the hypothalamus. We decreased the activity of CPT1 by administering to rats a ribozyme-containing plasmid designed specifically to decrease the expression of this enzyme or by infusing pharmacological inhibitors of its activity into the third cerebral ventricle. Either genetic or biochemical inhibition of hypothalamic CPT1 activity was sufficient to substantially diminish food intake and endogenous glucose production. These results indicated that changes in the rate of lipid oxidation in selective hypothalamic neurons signaled nutrient availability to the hypothalamus, which in turn modulated the exogenous and endogenous inputs of nutrients into the circulation.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Accessions

GenBank/EMBL/DDBJ

References

  1. 1.

    & Environmental contributions to obesity epidemic. Science 280, 1371–1374 (1998).

  2. 2.

    & Diabetes. Exploding type II. Lancet 352 (suppl. 4), SIV5 (1998).

  3. 3.

    , , & Chronic intracerebroventricular infusion of insulin reduces food intake and body weight of baboons. Nature. 282, 503–505 (1979).

  4. 4.

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

  5. 5.

    Obesity in the new millennium. Nature 404, 632–634 (2000).

  6. 6.

    et al. Small molecule insulin mimetics reduce food intake and body weight and prevent development of obesity. Nat. Med. 8, 179–183 (2002).

  7. 7.

    , , , & Central nervous system control of food intake. Nature 404, 661–671 (2000).

  8. 8.

    et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

  9. 9.

    , , , & A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393, 684–688 (1998).

  10. 10.

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

  11. 11.

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

  12. 12.

    et al. Cerulenin mimics effects of leptin on metabolic rate, food intake, and body weight independent of the melanocortin system, but unlike leptin, cerulenin fails to block neuroendocrine effects of fasting. Diabetes 50, 733–739 (2001).

  13. 13.

    , & Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc. Natl. Acad. Sci. USA 99, 66–71 (2002).

  14. 14.

    , & A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J. Clin. Invest. 60, 265–270 (1977).

  15. 15.

    Regulation of ketone body metabolism. A cellular perspective. Diabetes Rev. 2, 132–155 (1994).

  16. 16.

    et al. Central melanocortin receptors regulate insulin action. J. Clin. Invest. 108, 1079–1085 (2001).

  17. 17.

    et al. Intracerebroventricular (ICV) leptin regulates hepatic but not peripheral glucose fluxes. J. Biol. Chem. 273, 31160–31167 (1998).

  18. 18.

    , & Utilization of plasma fatty acid in rat brain: distribution of [14C]palmitate between oxidative and synthetic pathways. J. Neurochem. 49, 1507–1514 (1987).

  19. 19.

    & Fatty acids profiles of various lipids in the cerebrospinal fluid. Proc. Exp. Biol. Med. 136, 1294–1296 (1971).

  20. 20.

    et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long chain fatty acids. J. Biol. Chem. 278, 11303–11311 (2003).

  21. 21.

    , & Inhibition of rat liver acetyl coenzyme A carboxylase by long chain acyl coenzyme A and fatty acid. J. Biol. Chem. 252, 5483–5487 (1977).

  22. 22.

    , , & Long-chain fatty acids inhibit acetyl-CoA carboxylase gene expression in the pancreatic beta-cell line INS-1. Diabetes 46, 393–400 (1997).

  23. 23.

    , , , & The stimulation of ketogenesis by cannabinoids in cultured astrocytes defines carnitine palmitoyltransferase I as a new ceramide-activated enzyme. J. Neurochem. 72, 1759–1768 (1999).

  24. 24.

    et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature 410, 822–825 (2001).

  25. 25.

    , , , & Cloning, sequencing, and expression of a cDNA encoding rat liver carnitine palmitoyltransferase I. Direct evidence that a single polypeptide is involved in inhibitor interaction and catalytic function. J. Biol. Chem. 268, 5817–5822 (1993).

  26. 26.

    , & The structure, function and application of the hammerhead ribozyme. Eur. J. Biochem. 245, 1–16 (1997).

  27. 27.

    et al. A versatile vector for gene and oligonucleotide transfer into cells in culture and in vivo: polyethylenimine. Proc. Natl. Acad. Sci. USA 92, 7297–7301 (1995).

  28. 28.

    et al. Size, diffusibility and transfection performance of linear PEI/DNA complexes in the mouse central nervous system. Gene Ther. 5, 712–717 (1998).

  29. 29.

    Isolated removal of hypothalamic or other brain nuclei of the rat. Brain Res. 59, 449–450 (1973).

  30. 30.

    , , , & Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. Nat. Neurosci. 5, 566–572 (2002).

  31. 31.

    & The Rat Brain in Stereotaxic Coordinates 3rd edn. (Academic Press, 1997).

  32. 32.

    et al. Evidence for the involvement of carnitine-dependent long-chain acyltransferases in neuronal triglyceride and phospholipid fatty acid turnover. J. Neurochem. 62, 1530–1538 (1994).

  33. 33.

    , , , & Extraction of tissue long-chain acyl-CoA esters and measurement by reverse-phase high-performance liquid chromatography. Anal. Biochem. 150, 8–12 (1985).

Download references

Acknowledgements

This work was supported by grants from the National Institutes of Health (to L.R.; DK48321 and DK45024) and from the Albert Einstein College of Medicine Diabetes Research & Training Center. S.O. was the recipient of a post-doctoral fellowship and a Junior Faculty Award from the American Diabetes Association.

Author information

Author notes

    • Arduino Arduini

    Present address: F. Hoffmann-La Roche Ltd., Pharmaceutical Division, Vascular & Metabolic Diseases, CH-4070 Basel, Switzerland.

Affiliations

  1. Departments of Medicine and Molecular Pharmacology, Diabetes Research and Training Center, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, New York 10461, USA.

    • Silvana Obici
    • , Zhaohui Feng
    •  & Luciano Rossetti
  2. Department of Metabolism & Endocrinology, Sigma Tau Pharmaceutical Industries, Via Pontina km 30,400, 00040 Pomezia, Italy.

    • Arduino Arduini
    •  & Roberto Conti

Authors

  1. Search for Silvana Obici in:

  2. Search for Zhaohui Feng in:

  3. Search for Arduino Arduini in:

  4. Search for Roberto Conti in:

  5. Search for Luciano Rossetti in:

Competing interests

A.A. and R.C. are employed by a drug company and they may have interest in the development of ST1326 as a potential treatment for diabetes or obesity.

Corresponding author

Correspondence to Luciano Rossetti.

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nm873

Further reading