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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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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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The authors declare no competing financial interests.

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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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