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Hypothalamic sensing of fatty acids

Nature Neuroscience volume 8, pages 579–584 (2005)Cite this article

Abstract

Selective regions of the brain, including the hypothalamus, are capable of gathering information on the body's nutritional status in order to implement appropriate behavioral and metabolic responses to changes in fuel availability. This review focuses on direct metabolic signaling within the hypothalamus. There is growing evidence supporting the idea that fatty acid metabolism within discrete hypothalamic regions can function as a sensor for nutrient availability that can integrate multiple nutritional and hormonal signals.

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Figure 1: Delivery and metabolism of fatty acids in the hypothalamus.

Debbie Maizels

Figure 2: Hypothalamic regulation of LCFA-CoA levels.

Debbie Maizels

Figure 3: Convergence of nutritional and endocrine signals on hypothalamic LCFA-CoA.

Debbie Maizels

References

  1. Moran, T.H. & Schwartz, G.J. Neurobiology of cholecystokinin. Crit. Rev. Neurobiol. 9, 1–28 (1994).

    CAS  PubMed  Google Scholar 

  2. Gibbs, J., Young, R.C. & Smith, G.P. Cholecystokinin decreases food intake in rats. J. Comp. Physiol. Psychol. 84, 488–495 (1973).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. 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 

  6. Davis, J.D., Wirtshafter, D., Asin, K.E. & Brief, D. Sustained intracerebroventricular infusion of brain fuels reduces body weight and food intake in rats. Science 212, 81–83 (1981).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  9. Kennedy, G.C. The role of a depot fat in the hypothalamic control of food intake in the rat. Proc. R. Soc. Lond. B 140, 578–592 (1953).

    Article  CAS  Google Scholar 

  10. 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 

  11. Mayer, J. Glucostatic mechanism of regulation of food intake. N. Engl. J. Med. 249, 13–16 (1953).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. 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 

  15. 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 

  16. 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 

  17. Wang, J., Liu, R., Hawkins, M., Barzilai, N. & Rossetti, L. A nutrient-sensing pathway regulates leptin gene expression in muscle and fat. Nature 393, 684–688 (1998).

    Article  CAS  Google Scholar 

  18. Wang, J. et al. The effect of leptin on Lep expression is tissue-specific and nutritionally regulated. Nat. Med. 5, 895–899 (1999).

    Article  CAS  Google Scholar 

  19. 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 

  20. Woods, S.C., Seeley, R.J., Porte, D. Jr & Schwartz, M.W. Signals that regulate food intake and energy homeostasis. Science 280, 1378–1383 (1998).

    Article  CAS  Google Scholar 

  21. Mayer, J. Genetic, traumatic and environmental factors in the etiology of obesity. Physiol. Rev. 33, 472–508 (1953).

    Article  CAS  Google Scholar 

  22. Mayer, J. Regulation of energy intake and the body weight: the glucostatic theory and the lipostatic hypothesis. Ann. NY Acad. Sci. 63, 15–43 (1955).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. MacDonald, M.J. Elusive proximal signals of beta-cells for insulin secretion. Diabetes 39, 1461–1466 (1990).

    Article  CAS  Google Scholar 

  25. Hedeskov, C.J. Mechanism of glucose-induced insulin secretion. Physiol. Rev. 60, 442–509 (1980).

    Article  CAS  Google Scholar 

  26. Van Itallie, T.B., Beaudoin, R. & Mayer, J. Arteriovenous glucose differences, metabolic hypoglycemia and food intake in man. Am. J. Clin. Nutr. 1, 208–217 (1953).

    Article  CAS  Google Scholar 

  27. Walls, E.K. & Koopmans, H.S. Effect of intravenous nutrient infusions on food intake in rats. Physiol. Behav. 45, 1223–1226 (1989).

    Article  CAS  Google Scholar 

  28. Woods, S.C., Stein, L.J., McKay, L.D. & Porte, D. Jr. Suppression of food intake by intravenous nutrients and insulin in the baboon. Am. J. Physiol. 247, R393–R401 (1984).

    CAS  Google Scholar 

  29. Kanarek, R.B. & Mayer, J. 2-Deoxy-D-glucose induced feeding: relation to diet palatability. Pharmacol. Biochem. Behav. 8, 615–617 (1978).

    Article  CAS  Google Scholar 

  30. Smith, G.P. & Epstein, A.N. Increased feeding in response to decreased glucose utilization in the rat and monkey. Am. J. Physiol. 217, 1083–1087 (1969).

    Article  CAS  Google Scholar 

  31. Saladin, R. et al. Transient increase in obese gene expression after food intake or insulin administration. Nature 377, 527–529 (1995).

    Article  CAS  Google Scholar 

  32. Qi, K., Hall, M. & Deckelbaum, R.J. Long-chain polyunsaturated fatty acid accretion in brain. Curr. Opin. Clin. Nutr. Metab. Care 5, 133–138 (2002).

    Article  CAS  Google Scholar 

  33. Rapoport, S.I. In vivo fatty acid incorporation into brain phosholipids in relation to plasma availability, signal transduction and membrane remodeling. J. Mol. Neurosci. 16, 243–261 (2001).

    Article  CAS  Google Scholar 

  34. Rapoport, S.I. In vivo labeling of brain phospholipids by long-chain fatty acids: relation to turnover and function. Lipids 31 (Suppl.), S97–S101 (1996).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Goto, M. & Spitzer, J.J. Fatty acid profiles of various lipids in the cerebrospinal fluid. Proc. Soc. Exp. Biol. Med. 136, 1294–1296 (1971).

    Article  CAS  Google Scholar 

  37. Ruderman, N.B., Saha, A.K., Vavvas, D., Heydrick, S.J. & Kurowski, T.G. Lipid abnormalities in muscle of insulin-resistant rodents. The malonyl CoA hypothesis. Ann. NY Acad. Sci. 827, 221–230 (1997).

    Article  CAS  Google Scholar 

  38. McGarry, J.D., Mannaerts, G.P. & Foster, D.W. A possible role for malonyl-CoA in the regulation of hepatic fatty acid oxidation and ketogenesis. J. Clin. Invest. 60, 265–270 (1977).

    Article  CAS  Google Scholar 

  39. Monnikes, H. et al. Pathways of Fos expression in locus ceruleus, dorsal vagal complex, and PVN in response to intestinal lipid. Am. J. Physiol. 273, R2059–R2071 (1997).

    CAS  PubMed  Google Scholar 

  40. Matzinger, D. et al. The role of long chain fatty acids in regulating food intake and cholecystokinin release in humans. Gut 46, 688–693 (2000).

    Article  CAS  Google Scholar 

  41. Schwartz, G.J., Whitney, A., Skoglund, C., Castonguay, T.W. & Moran, T.H. Decreased responsiveness to dietary fat in Otsuka Long-Evans Tokushima fatty rats lacking CCK-A receptors. Am. J. Physiol. 277, R1144–R1151 (1999).

    CAS  PubMed  Google Scholar 

  42. Morgan, K., Obici, S. & Rossetti, L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J. Biol. Chem. 279, 31139–31148 (2004).

    Article  CAS  Google Scholar 

  43. 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 

  44. Beverly, J.L. & Martin, R.J. Influence of fatty acid oxidation in lateral hypothalamus on food intake and body composition. Am. J. Physiol. 261, R339–R343 (1991).

    CAS  PubMed  Google Scholar 

  45. Hardie, D.G. & Carling, D. The AMP-activated protein kinase—fuel gauge of the mammalian cell? Eur. J. Biochem. 246, 259–273 (1997).

    Article  CAS  Google Scholar 

  46. 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 

  47. Kemp, B.E. et al. Dealing with energy demand: the AMP-activated protein kinase. Trends Biochem. Sci. 24, 22–25 (1999).

    Article  CAS  Google Scholar 

  48. 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 

  49. Andersson, U. et al. AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279, 12005–12008 (2004).

    Article  CAS  Google Scholar 

  50. 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 

  51. Gao, S. & Lane, M.D. Effect of the anorectic fatty acid synthase inhibitor C75 on neuronal activity in the hypothalamus and brainstem. Proc. Natl. Acad. Sci. USA 100, 5628–5633 (2003).

    Article  CAS  Google Scholar 

  52. Kim, E.K. et al. Expression of FAS within hypothalamic neurons: a model for decreased food intake after C75 treatment. Am. J. Physiol. Endocrinol. Metab. 283, E867–E879 (2002).

    Article  CAS  Google Scholar 

  53. Clegg, D.J., Wortman, M.D., Benoit, S.C., McOsker, C.C. & Seeley, R.J. Comparison of central and peripheral administration of C75 on food intake, body weight, and conditioned taste aversion. Diabetes 51, 3196–3201 (2002).

    Article  CAS  Google Scholar 

  54. Makimura, H. 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).

    Article  CAS  Google Scholar 

  55. Takahashi, K.A., Smart, J.L., Liu, H. & Cone, R.D. The anorexigenic fatty acid synthase inhibitor, C75, is a nonspecific neuronal activator. Endocrinology 145, 184–193 (2004).

    Article  CAS  Google Scholar 

  56. Miller, I., Ronnett, G.V., Moran, T.H. & Aja, S. Anorexigenic C75 alters c-Fos in mouse hypothalamic and hindbrain subnuclei. Neuroreport 15, 925–929 (2004).

    Article  CAS  Google Scholar 

  57. 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 

  58. Shimokawa, T., Kumar, M.V. & Lane, M.D. Effect of a fatty acid synthase inhibitor on food intake and expression of hypothalamic neuropeptides. Proc. Natl. Acad. Sci. USA 99, 66–71 (2002).

    Article  CAS  Google Scholar 

  59. Kim, E.K. et al. C75, a fatty acid synthase inhibitor, reduces food intake via hypothalamic AMP-activated protein kinase. J. Biol. Chem. 279, 19970–19976 (2004).

    Article  CAS  Google Scholar 

  60. Thupari, J.N., Landree, L.E., Ronnett, G.V. & Kuhajda, F.P. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. Proc. Natl. Acad. Sci. USA 99, 9498–9502 (2002).

    Article  CAS  Google Scholar 

  61. Landree, L.E. et al. C75, a fatty acid synthase inhibitor, modulates AMP-activated protein kinase to alter neuronal energy metabolism. J. Biol. Chem. 279, 3817–3827 (2004).

    Article  CAS  Google Scholar 

  62. Lavrentyev, E.N., Matta, S.G. & Cook, G.A. Expression of three carnitine palmitoyl-transferase-I isoforms in 10 regions of the rat brain during feeding, fasting, and diabetes. Biochem. Biophys. Res. Commun. 315, 174–178 (2004).

    Article  CAS  Google Scholar 

  63. Friedman, J.M. A war on obesity, not the obese. Science 299, 856–858 (2003).

    Article  CAS  Google Scholar 

  64. Hill, J.O. & Peters, J.C. Environmental contributions to the obesity epidemic. Science 280, 1371–1374 (1998).

    Article  CAS  Google Scholar 

  65. Ravussin, E. & Gautier, J.F. Metabolic predictors of weight gain. Int. J. Obes. Relat. Metab. Disord. 23 (Suppl. 1), 37–41 (1999).

    Article  Google Scholar 

  66. Wang, J. et al. Overfeeding rapidly induces leptin and insulin resistance. Diabetes 50, 2786–2791 (2001).

    Article  CAS  Google Scholar 

  67. Neel, J.V. The 'thrifty genotype' in 1998. Nutr. Rev. 57, S2–S9 (1999).

    Article  CAS  Google Scholar 

  68. Coleman, D.L. Obese and diabetes: two mutant genes causing diabetes-obesity syndromes in mice. Diabetologia 14, 141–148 (1978).

    Article  CAS  Google Scholar 

  69. Coleman, D.L. Obesity genes: beneficial effects in heterozygous mice. Science 203, 663–665 (1979).

    Article  CAS  Google Scholar 

  70. Kersten, S. Mechanisms of nutritional and hormonal regulation of lipogenesis. EMBO Rep. 2, 282–286 (2001).

    Article  CAS  Google Scholar 

  71. Cinti, S. et al. Immunohistochemical localization of leptin and uncoupling protein in white and brown adipose tissue. Endocrinology 138, 797–804 (1997).

    Article  CAS  Google Scholar 

  72. Frederich, R.C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314 (1995).

    Article  CAS  Google Scholar 

  73. Schwartz, M.W. et al. Specificity of leptin action on elevated blood glucose levels and hypothalamic neuropeptide Y gene expression in ob/ob mice. Diabetes 45, 531–535 (1996).

    Article  CAS  Google Scholar 

  74. Schwartz, M.W., Seeley, R.J., Campfield, L.A., Burn, P. & Baskin, D.G. Identification of targets of leptin action in rat hypothalamus. J. Clin. Invest. 98, 1101–1106 (1996).

    Article  CAS  Google Scholar 

  75. Brief, D.J. & Davis, J.D. Reduction of food intake and body weight by chronic intraventricular insulin infusion. Brain Res. Bull. 12, 571–575 (1984).

    Article  CAS  Google Scholar 

  76. 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 

  77. Widdowson, P.S., Upton, R., Buckingham, R., Arch, J. & Williams, G. Inhibition of food response to intracerebroventricular injection of leptin is attenuated in rats with diet-induced obesity. Diabetes 46, 1782–1785 (1997).

    Article  CAS  Google Scholar 

  78. Halaas, J.L. et al. Physiological response to long-term peripheral and central leptin infusion in lean and obese mice. Proc. Natl. Acad. Sci. USA 94, 8878–8883 (1997).

    Article  CAS  Google Scholar 

  79. Thupari, J.N., Landree, L.E., Ronnett, G.V. & Kuhajda, F.P. C75 increases peripheral energy utilization and fatty acid oxidation in diet-induced obesity. Proc. Natl. Acad. Sci. USA 99, 9498–9502 (2002).

    Article  CAS  Google Scholar 

  80. Kim, K.H., Lopez-Casillas, F., Bai, D.H., Luo, X. & Pape, M.E. Role of reversible phosphorylation of acetyl-CoA carboxylase in long-chain fatty acid synthesis. FASEB J. 3, 2250–2256 (1989).

    Article  CAS  Google Scholar 

  81. Witters, L.A. & Kemp, B.E. Insulin activation of acetyl-CoA carboxylase accompanied by inhibition of the 5′-AMP-activated protein kinase. J. Biol. Chem. 267, 2864–2867 (1992).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Skirball Institute, grants from the National Institutes of Health (to L.R.: DK45024, DK48321 and AG21654; to G.J.S.: DK47208) and grants from the Albert Einstein College of Medicine Diabetes Research & Training Center (DK20541). T.K.T. Lam is supported by a training grant from the National Institute of Aging (T32-AG023475).

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  1. Department of Medicine and Diabetes Research Center, Bronx, 10461, New York, USA

    Tony K T Lam, Gary J Schwartz & Luciano Rossetti

  2. Department of Molecular Pharmacology, and Department of Neuroscience, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Tony K T Lam & Luciano Rossetti

  3. Department of Neuroscience, Albert Einstein College of Medicine, Bronx, 10461, New York, USA

    Gary J Schwartz

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Correspondence to Luciano Rossetti.

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Lam, T., Schwartz, G. & Rossetti, L. Hypothalamic sensing of fatty acids. Nat Neurosci 8, 579–584 (2005). https://doi.org/10.1038/nn1456

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