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.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting file
Article and author information
Author details
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.
Metrics
-
- 7,553
- views
-
- 1,010
- downloads
-
- 80
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Further reading
-
- Neuroscience
During delayed ballistic reaches, motor areas consistently display movement-specific activity patterns prior to movement onset. It is unclear why these patterns arise: while they have been proposed to seed an initial neural state from which the movement unfolds, recent experiments have uncovered the presence and necessity of ongoing inputs during movement, which may lessen the need for careful initialization. Here, we modeled the motor cortex as an input-driven dynamical system, and we asked what the optimal way to control this system to perform fast delayed reaches is. We find that delay-period inputs consistently arise in an optimally controlled model of M1. By studying a variety of network architectures, we could dissect and predict the situations in which it is beneficial for a network to prepare. Finally, we show that optimal input-driven control of neural dynamics gives rise to multiple phases of preparation during reach sequences, providing a novel explanation for experimentally observed features of monkey M1 activity in double reaching.
-
- Neuroscience
Humans make irrational decisions in the presence of irrelevant distractor options. There is little consensus on whether decision making is facilitated or impaired by the presence of a highly rewarding distractor, or whether the distractor effect operates at the level of options’ component attributes rather than at the level of their overall value. To reconcile different claims, we argue that it is important to consider the diversity of people’s styles of decision making and whether choice attributes are combined in an additive or multiplicative way. Employing a multi-laboratory dataset investigating the same experimental paradigm, we demonstrated that people used a mix of both approaches and the extent to which approach was used varied across individuals. Critically, we identified that this variability was correlated with the distractor effect during decision making. Individuals who tended to use a multiplicative approach to compute value, showed a positive distractor effect. In contrast, a negative distractor effect (divisive normalisation) was prominent in individuals tending towards an additive approach. Findings suggest that the distractor effect is related to how value is constructed, which in turn may be influenced by task and subject specificities. This concurs with recent behavioural and neuroscience findings that multiple distractor effects co-exist.