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Effects of Leptin Deficiency and Replacement on Cerebellar Response to Food-Related Cues

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Abstract

Leptin affects eating behavior partly by altering the response of the brain to food-related stimuli. The effects of leptin on brain structure have been observed in the cerebellum, where leptin receptors are most densely expressed, but the function of leptin in the cerebellum remains unclear. We performed a nonrandomized, prospective interventional study of three adults with genetically mediated leptin deficiency. FMRI was recorded three times each year during years 5 and 6 of leptin replacement treatment. Session 1 of each year occurred after 10 months of continuous daily replacement, session 2 after 33–37 days without leptin, and session 3 at 14–23 days after daily replacement was restored. Statistical parametric mapping software (SPM5) was employed to contrast the fMRI blood oxygenation level-dependent response to images of high-calorie foods versus images of brick walls. Covariate analyses quantified the effects of the duration of leptin replacement and concomitant changes in body mass on the cerebral responses. Longer duration of replacement was associated with more activation by food images in a ventral portion of the posterior lobe of the cerebellum, while simultaneous decreases in body mass were associated with decreased activation in a more dorsal portion of the same lobe. These findings indicate that leptin replacement reversibly alters neural function within the posterior cerebellum and modulates plasticity-dependent brain physiology in response to food cues. The results suggest an underexplored role for the posterior cerebellum in the regulation of leptin-mediated processes related to food intake.

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Acknowledgments

During the course of this study Amgen, Inc. graciously provided leptin. Amylin, Inc. now provides leptin to these patients. Neither Amgen, Inc. nor Amylin, Inc. contributed to the design, analysis, or writing of this study. This study was supported in part by NIH grants K24RR016996, R01DK058851, and U01GM061394 (JL); K24RR017365 and R01DK063240 (M-LW); T32 DA024635 (EDL); and the UCLA GCRC (NIH grant M01RR00865 to G.S. Levy). GPF, M-LW and JL were supported by The Australian National University institutional funds. EDL was supported by endowments from the Thomas P. Pike and Katherine K. Chair in Addiction Studies and the Marjorie M. Greene Family Trust.

Conflict of Interest

The authors do not declare any potential conflicts of interest in this submission.

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Authors and Affiliations

  1. Department of Psychiatry and Biobehavioral Sciences and the Semel Institute, David Geffen School of Medicine, University of California Los Angeles, 760 Westwood Plaza, C8-831, Los Angeles, CA, 90024, USA

    Steven M. Berman, Milky Kohno & Edythe D. London

  2. Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, 90024, USA

    Edythe D. London

  3. Brain Research Institute, University of California Los Angeles, Los Angeles, CA, 90024, USA

    Steven M. Berman & Edythe D. London

  4. Department of Translational Medicine, John Curtin School of Medical Research, The Australian National University, Canberra, ACT, 0200, Australia

    Gilberto Paz-Filho, Ma-Li Wong & Julio Licinio

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  1. Steven M. Berman
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  2. Gilberto Paz-Filho
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  3. Ma-Li Wong
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  4. Milky Kohno
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  5. Julio Licinio
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  6. Edythe D. London
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Correspondence to Edythe D. London.

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Julio Licinio and Edythe D. London contributed equally as senior authors.

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Berman, S.M., Paz-Filho, G., Wong, ML. et al. Effects of Leptin Deficiency and Replacement on Cerebellar Response to Food-Related Cues. Cerebellum 12, 59–67 (2013). https://doi.org/10.1007/s12311-012-0360-z

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