POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels
- University of Texas Southwestern Medical Center, United States
- Howard Community College, United States
- University of Texas Health Science Center at San Antonio, United States
Abstract
Leptin is critical for energy balance, glucose homeostasis, and for metabolic and neuroendocrine adaptations to starvation. A prevalent model predicts that leptin's actions are mediated through pro-opiomelanocortin (POMC) neurons that express leptin receptors (LEPRs). However, previous studies have used prenatal genetic manipulations, which may be subject to developmental compensation. Here, we tested the direct contribution of POMC neurons expressing LEPRs in regulating energy balance, glucose homeostasis and leptin secretion during fasting using a spatiotemporally controlled Lepr expression mouse model. We report a dissociation between leptin's effects on glucose homeostasis versus energy balance in POMC neurons. We show that these neurons are dispensable for regulating food intake, but are required for coordinating hepatic glucose production and for the fasting-induced fall in leptin levels, independent of changes in fat mass. We also identify a role for sympathetic nervous system regulation of the inhibitory adrenergic receptor (ADRA2A) in regulating leptin production. Collectively, our findings highlight a previously unrecognized role of POMC neurons in regulating leptin levels.
Article and author information
Author details
Funding
National Institute of Diabetes and Digestive and Kidney Diseases (R37DK053301)
- Joel K Elmquist
Canadian Diabetes Association (NOD_PF-3-15-4756-AC)
- Alexandre Caron
American Heart Association (14SDG17950008)
- Teppei Fujikawa
National Institute of Diabetes and Digestive and Kidney Diseases (K01DK11164401)
- Carlos M Castorena
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK114036)
- Chen Liu
American Heart Association (16SDG27260001)
- Chen Liu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Richard D Palmiter, Howard Hughes Medical Institute, University of Washington, United States
Ethics
Animal experimentation: Animal work described in this manuscript has been approved and conducted under the oversight of the UT Southwestern Institutional Animal Care and Use Committee (IACUC, APN 2015-101301 and APN 2015-101263).
Version history
- Received: November 20, 2017
- Accepted: March 8, 2018
- Accepted Manuscript published: March 12, 2018 (version 1)
- Version of Record published: March 23, 2018 (version 2)
Copyright
© 2018, Caron 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
-
- 4,715
- views
-
- 701
- downloads
-
- 77
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
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)
POMC neurons expressing leptin receptors coordinate metabolic responses to fasting via suppression of leptin levels
eLife 7:e33710.
https://doi.org/10.7554/eLife.33710
Further reading
-
- Neuroscience
Synaptic inputs to cortical neurons are highly structured in adult sensory systems, such that neighboring synapses along dendrites are activated by similar stimuli. This organization of synaptic inputs, called synaptic clustering, is required for high-fidelity signal processing, and clustered synapses can already be observed before eye opening. However, how clustered inputs emerge during development is unknown. Here, we employed concurrent in vivo whole-cell patch-clamp and dendritic calcium imaging to map spontaneous synaptic inputs to dendrites of layer 2/3 neurons in the mouse primary visual cortex during the second postnatal week until eye opening. We found that the number of functional synapses and the frequency of transmission events increase several fold during this developmental period. At the beginning of the second postnatal week, synapses assemble specifically in confined dendritic segments, whereas other segments are devoid of synapses. By the end of the second postnatal week, just before eye opening, dendrites are almost entirely covered by domains of co-active synapses. Finally, co-activity with their neighbor synapses correlates with synaptic stabilization and potentiation. Thus, clustered synapses form in distinct functional domains presumably to equip dendrites with computational modules for high-capacity sensory processing when the eyes open.
-
- Neuroscience
Accurate tracking of the same neurons across multiple days is crucial for studying changes in neuronal activity during learning and adaptation. Advances in high-density extracellular electrophysiology recording probes, such as Neuropixels, provide a promising avenue to accomplish this goal. Identifying the same neurons in multiple recordings is, however, complicated by non-rigid movement of the tissue relative to the recording sites (drift) and loss of signal from some neurons. Here, we propose a neuron tracking method that can identify the same cells independent of firing statistics, that are used by most existing methods. Our method is based on between-day non-rigid alignment of spike-sorted clusters. We verified the same cell identity in mice using measured visual receptive fields. This method succeeds on datasets separated from 1 to 47 days, with an 84% average recovery rate.
