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PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans

Abstract

The ability to maintain adequate nutrient intake is critical for survival. Complex interrelated neuronal circuits have developed in the mammalian brain to regulate many aspects of feeding behaviour, from food-seeking to meal termination. The hypothalamus and brainstem are thought to be the principal homeostatic brain areas responsible for regulating body weight1,2. However, in the current ‘obesogenic’ human environment food intake is largely determined by non-homeostatic factors including cognition, emotion and reward, which are primarily processed in corticolimbic and higher cortical brain regions3. Although the pleasure of eating is modulated by satiety and food deprivation increases the reward value of food, there is currently no adequate neurobiological account of this interaction between homeostatic and higher centres in the regulation of food intake in humans1,4,5. Here we show, using functional magnetic resonance imaging, that peptide YY3–36 (PYY), a physiological gut-derived satiety signal, modulates neural activity within both corticolimbic and higher-cortical areas as well as homeostatic brain regions. Under conditions of high plasma PYY concentrations, mimicking the fed state, changes in neural activity within the caudolateral orbital frontal cortex predict feeding behaviour independently of meal-related sensory experiences. In contrast, in conditions of low levels of PYY, hypothalamic activation predicts food intake. Thus, the presence of a postprandial satiety factor switches food intake regulation from a homeostatic to a hedonic, corticolimbic area. Our studies give insights into the neural networks in humans that respond to a specific satiety signal to regulate food intake. An increased understanding of how such homeostatic and higher brain functions are integrated may pave the way for the development of new treatment strategies for obesity.

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Figure 1: Effect of infusions on plasma PYY concentrations and food intake.
Figure 2: Brain areas modulated by PYY.
Figure 3: Hypothalamic and OFC response to PYY and predictive effect on subsequent caloric intake.

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References

  1. Morton, G. J., Cummings, D. E., Baskin, D. G., Barsh, G. S. & Schwartz, M. W. Central nervous system control of food intake and body weight. Nature 443, 289–295 (2006)

    Article  ADS  CAS  Google Scholar 

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

    Article  ADS  CAS  Google Scholar 

  3. Berthoud, H. R. Neural control of appetite: cross-talk between homeostatic and non-homeostatic systems. Appetite 43, 315–317 (2004)

    Article  Google Scholar 

  4. Fulton, S., Woodside, B. & Shizgal, P. Modulation of brain reward circuitry by leptin. Science 287, 125–128 (2000)

    Article  ADS  CAS  Google Scholar 

  5. Saper, C. B., Chou, T. C. & Elmquist, J. K. The need to feed: homeostatic and hedonic control of eating. Neuron 36, 199–211 (2002)

    Article  CAS  Google Scholar 

  6. Liu, Y., Gao, J. H., Liu, H. L. & Fox, P. T. The temporal response of the brain after eating revealed by functional MRI. Nature 405, 1058–1062 (2000)

    Article  ADS  CAS  Google Scholar 

  7. Small, D. M., Zatorre, R. J., Dagher, A., Evans, A. C. & Jones-Gotman, M. Changes in brain activity related to eating chocolate: from pleasure to aversion. Brain 124, 1720–1733 (2001)

    Article  CAS  Google Scholar 

  8. Tataranni, P. A. et al. Neuroanatomical correlates of hunger and satiation in humans using positron emission tomography. Proc. Natl Acad. Sci. USA 96, 4569–4574 (1999)

    Article  ADS  CAS  Google Scholar 

  9. Smeets, P. A. et al. Effect of satiety on brain activation during chocolate tasting in men and women. Am. J. Clin. Nutr. 83, 1297–1305 (2006)

    Article  CAS  Google Scholar 

  10. DelParigi, A. et al. Persistence of abnormal neural responses to a meal in postobese individuals. Int. J. Obes. Relat. Metab. Disord. 28, 370–377 (2004)

    Article  CAS  Google Scholar 

  11. Cummings, D. E. & Overduin, J. Gastrointestinal regulation of food intake. J. Clin. Invest. 117, 13–23 (2007)

    Article  CAS  Google Scholar 

  12. Badman, M. K. & Flier, J. S. The gut and energy balance: visceral allies in the obesity wars. Science 307, 1909–1914 (2005)

    Article  ADS  CAS  Google Scholar 

  13. Batterham, R. L. et al. Gut hormone PYY3–36 physiologically inhibits food intake. Nature 418, 650–654 (2002)

    Article  ADS  CAS  Google Scholar 

  14. Batterham, R. L. et al. Inhibition of food intake in obese subjects by peptide YY3–36. N. Engl. J. Med. 349, 941–948 (2003)

    Article  CAS  Google Scholar 

  15. Wren, A. M. et al. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992–5995 (2001)

    Article  CAS  Google Scholar 

  16. Chan, J. L., Stoyneva, V., Kelesidis, T., Raciti, P. & Mantzoros, C. S. Peptide YY levels are decreased by fasting and elevated following caloric intake but are not regulated by leptin. Diabetologia 49, 169–173 (2006)

    Article  CAS  Google Scholar 

  17. le Roux, C. W. et al. Attenuated peptide YY release in obese subjects is associated with reduced satiety. Endocrinology 147, 3–8 (2006)

    Article  ADS  CAS  Google Scholar 

  18. Batterham, R. L. et al. Critical role for peptide YY in protein-mediated satiation and body-weight regulation. Cell Metab. 4, 223–233 (2006)

    Article  CAS  Google Scholar 

  19. Abbott, C. R. et al. The inhibitory effects of peripheral administration of peptide YY3–36 and glucagon-like peptide-1 on food intake are attenuated by ablation of the vagal-brainstem-hypothalamic pathway. Brain Res. 1044, 127–131 (2005)

    Article  ADS  CAS  Google Scholar 

  20. Abizaid, A. et al. Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. J. Clin. Invest. 116, 3229–3239 (2006)

    Article  CAS  Google Scholar 

  21. Fulton, S. et al. Leptin regulation of the mesoaccumbens dopamine pathway. Neuron 51, 811–822 (2006)

    Article  CAS  Google Scholar 

  22. Kringelbach, M. L. Food for thought: hedonic experience beyond homeostasis in the human brain. Neuroscience 126, 807–819 (2004)

    Article  CAS  Google Scholar 

  23. Kringelbach, M. L. The human orbitofrontal cortex: linking reward to hedonic experience. Nature Rev. Neurosci. 6, 691–702 (2005)

    Article  CAS  Google Scholar 

  24. Kringelbach, M. L., O’Doherty, J., Rolls, E. T. & Andrews, C. Activation of the human orbitofrontal cortex to a liquid food stimulus is correlated with its subjective pleasantness. Cereb. Cortex 13, 1064–1071 (2003)

    Article  CAS  Google Scholar 

  25. Wang, G. J. et al. Exposure to appetitive food stimuli markedly activates the human brain. Neuroimage 21, 1790–1797 (2004)

    Article  Google Scholar 

  26. Gautier, J. F. et al. Effect of satiation on brain activity in obese and lean women. Obes. Res. 9, 676–684 (2001)

    Article  CAS  Google Scholar 

  27. Hinton, E. C. et al. Neural contributions to the motivational control of appetite in humans. Eur. J. Neurosci. 20, 1411–1418 (2004)

    Article  Google Scholar 

  28. Rolls, E. T. The functions of the orbitofrontal cortex. Brain Cogn. 55, 11–29 (2004)

    Article  Google Scholar 

  29. Delparigi, A. et al. Successful dieters have increased neural activity in cortical areas involved in the control of behavior. Int. J. Obes. (Lond.) 31, 440–448 (2006)

    Article  Google Scholar 

  30. Whitwell, J. L. et al. VBM signatures of abnormal eating behaviours in frontotemporal lobar degeneration. Neuroimage 35, 207–213 (2007)

    Article  Google Scholar 

  31. Flint, A., Raben, A., Blundell, J. E. & Astrup, A. Reproducibility, power and validity of visual analogue scales in assessment of appetite sensations in single test meal studies. Int. J. Obes. Relat. Metab. Disord. 24, 38–48 (2000)

    Article  CAS  Google Scholar 

  32. Batterham, R. L. et al. Pancreatic polypeptide reduces appetite and food intake in humans. J. Clin. Endocrinol. Metab. 88, 3989–3992 (2003)

    Article  CAS  Google Scholar 

  33. Rosenthal, J. M. et al. The effect of acute hypoglycemia on brain function and activation: a functional magnetic resonance imaging study. Diabetes 50, 1618–1626 (2001)

    Article  CAS  Google Scholar 

  34. Rosenthal, M. J. et al. Caffeine restores regional brain activation in acute hypoglycaemia in healthy volunteers. Diabet. Med. 24, 720–727 (2007)

    Article  CAS  Google Scholar 

  35. Deichmann, R., Gottfried, J. A., Hutton, C. & Turner, R. Optimized EPI for fMRI studies of the orbitofrontal cortex. Neuroimage 19, 430–441 (2003)

    Article  CAS  Google Scholar 

  36. Friston, K. J., Holmes, A., Poline, J. B., Price, C. J. & Frith, C. D. Detecting activations in PET and fMRI: levels of inference and power. Neuroimage 4, 223–235 (1996)

    Article  CAS  Google Scholar 

  37. Talairach, J. & Tournoux, P. Co-planar Stereotaxic Atlas of the Human Brain (Thieme, Stuttgart, 1988)

    Google Scholar 

  38. Paxinos, G. & Huang, X. Atlas of the Human Brainstem (Academic Press, San Diego, 1995)

    Google Scholar 

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Acknowledgements

We thank the subjects who participated in this study. We also thank J. Jones and E. Robins for assistance with RIAs; Y. Shaham and H.-R. Berthoud for discussions; and C. Andrew, D. Gasston and the radiography team for technical assistance. This work was supported by the Medical Research Council, Rosetrees Trust and the Travers’ Legacy. R.L.B. is an MRC Clinician Scientist.

Author Contributions All authors designed the research. R.L.B., J.M.R. and F.O.Z. undertook the patient studies. R.L.B. analysed the plasma samples. F.O.Z., J.M.R., R.L.B. and D.H.F. analysed the fMRI data. All authors contributed to writing the manuscript.

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Correspondence to Rachel L. Batterham.

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This file contains Supplementary Tables S1-S4 and Supplementary Figures S1-S12 with Legends. (PDF 536 kb)

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Batterham, R., ffytche, D., Rosenthal, J. et al. PYY modulation of cortical and hypothalamic brain areas predicts feeding behaviour in humans. Nature 450, 106–109 (2007). https://doi.org/10.1038/nature06212

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