Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat
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.
Article and author information
Author details
Lisa R Beutler
Department of Physiology, University of California, San Francisco, San Francisco, United States
Competing interests
The authors declare that no competing interests exist.
Timothy V Corpuz
Department of Physiology, University of California, San Francisco, San Francisco, United States
Competing interests
The authors declare that no competing interests exist.
Jamie S Ahn
Department of Physiology, University of California, San Francisco, San Francisco, United States
Competing interests
The authors declare that no competing interests exist.
Seher Kosar
Department of Physiology, University of California, San Francisco, San Francisco, United States
Competing interests
The authors declare that no competing interests exist.
Weimin Song
Feinberg School of Medicine, Northwestern University, Chicago, United States
Competing interests
The authors declare that no competing interests exist.
Yiming Chen
Department of Physiology, University of California, San Francisco, San Francisco, United States
Competing interests
The authors declare that no competing interests exist.
Funding
National Institutes of Health (R01DK106399)
National Institutes of Health (R01NS094781)
National Institutes of Health (DP2DK021153)
Howard Hughes Medical Institute (Investigator)
American Diabetes Association (Pathway Award)
New York Stem Cell Foundation (Robertson Investigator Award)
Rita Allen Foundation (Scholar Award)
National Institutes of Health (K08DK118188)
National Institutes of Health (P30 DK063720)
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)
Reviewing Editor
Joel K Elmquist, University of Texas Southwestern Medical Center, United States
Publication history
Received: February 10, 2020
Accepted: July 20, 2020
Accepted Manuscript published: July 28, 2020 (version 1)
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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