Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat
- University of California, San Francisco, United States
- Northwestern University, United States
Abstract
Body weight is regulated by interoceptive neural circuits that track energy need, but how the activity of these circuits is altered in obesity remains poorly understood. Here we describe the in vivo dynamics of hunger-promoting AgRP neurons during the development of diet-induced obesity in mice. We show that high-fat diet attenuates the response of AgRP neurons to an array of nutritionally-relevant stimuli including food cues, intragastric nutrients, cholecystokinin and ghrelin. These alterations are are specific to dietary fat but not carbohydrate or protein. Subsequent weight loss restores the responsiveness of AgRP neurons to exterosensory cues but fails to rescue their sensitivity to gastrointestinal hormones or nutrients. These findings reveal that obesity triggers broad dysregulation of hypothalamic hunger neurons that is incompletely reversed by weight loss and may contribute to the difficulty of maintaining a reduced weight.
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All data generated or analysed during this study are included in the manuscript and supporting file
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Funding
National Institutes of Health (R01DK106399)
- Zachary A Knight
National Institutes of Health (R01NS094781)
- Zachary A Knight
National Institutes of Health (DP2DK021153)
- Zachary A Knight
Howard Hughes Medical Institute (Investigator)
- Zachary A Knight
American Diabetes Association (Pathway Award)
- Zachary A Knight
New York Stem Cell Foundation (Robertson Investigator Award)
- Zachary A Knight
Rita Allen Foundation (Scholar Award)
- Zachary A Knight
National Institutes of Health (K08DK118188)
- Lisa R Beutler
National Institutes of Health (P30 DK063720)
- Lisa R Beutler
The funders played no role in the design or interpretation of the work.
Ethics
Animal experimentation: Experimental protocols were approved by the University of California, San Francisco IACUC following the National Institutes of Health guidelines for the Care and Use of Laboratory Animals. (protocol# AN179674)
Copyright
© 2020, Beutler et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat
eLife 9:e55909.
https://doi.org/10.7554/eLife.55909
