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Journal Article•DOI•

Rapid, reversible activation of AgRP neurons drives feeding behavior in mice

Michael J. Krashes1, Shuichi Koda2, Chian Ping Ye2, Sarah C. Rogan3, Andrew C. Adams2, Daniel S. Cusher2, Eleftheria Maratos-Flier2, Bryan L. Roth3, Bradford B. Lowell2 •
Beth Israel Deaconess Medical Center1, Harvard University2, University of North Carolina at Chapel Hill3
01 Apr 2011-Journal of Clinical Investigation (American Society for Clinical Investigation)-Vol. 121, Iss: 4, pp 1424-1428
TL;DR: Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, it is demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores.
Abstract: Several different neuronal populations are involved in regulating energy homeostasis. Among these, agouti-related protein (AgRP) neurons are thought to promote feeding and weight gain; however, the evidence supporting this view is incomplete. Using designer receptors exclusively activated by designer drugs (DREADD) technology to provide specific and reversible regulation of neuronal activity in mice, we have demonstrated that acute activation of AgRP neurons rapidly and dramatically induces feeding, reduces energy expenditure, and ultimately increases fat stores. All these effects returned to baseline after stimulation was withdrawn. In contrast, inhibiting AgRP neuronal activity in hungry mice reduced food intake. Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding. Of interest, activating AgRP neurons potently increased motivation for feeding and also drove intense food-seeking behavior, demonstrating that AgRP neurons engage brain sites controlling multiple levels of feeding behavior. Due to its ease of use and suitability for both acute and chronic regulation, DREADD technology is ideally suited for investigating the neural circuits hypothesized to regulate energy balance.

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Citations
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Journal Article•DOI•
Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet

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Patricia E. Bunney1, Anastasia N. Zink1, A. A. Holm1, Charles J. Billington1, Catherine M. Kotz1 •
University of Minnesota1
01 Jul 2017-Physiology & Behavior
TL;DR: A change in the efficiency of energy expenditure based upon diet is suggested, such that SPA during HFD burns fewer calories compared to SPA on a standard chow diet.

1,444 citations

Cites background from "Rapid, reversible activation of AgR..."

  • ...AC CE PT ED M AN US CR IP T targeted infusions of orexin and/or orexin agonists into the brain, the use of DREADDs allows for the sustained activation of these neurons on the order of hours without needing to inject directly into the brain [17, 18]....

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Journal Article•DOI•
DREADDs for Neuroscientists.

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Bryan L. Roth1•
University of North Carolina at Chapel Hill1
17 Feb 2016-Neuron
TL;DR: A primer on DREADDs is provided highlighting key technical and conceptual considerations and identify challenges for chemogenetics going forward.

1,145 citations

Cites background or methods from "Rapid, reversible activation of AgR..."

  • ...Since then, hM3Dq has been widely used to enhance neuronal firing, and I here cite only representative examples in which feeding (Krashes et al., 2011; Atasoy et al., 2012), energy expenditure (Kong et al., 2012), locomotion and striatal synaptogenesis (Kozorovitskiy et al., 2012), memory (Garner…...

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  • ...AgRP Neurons hM3Dq (Krashes et al., 2011) ChR2 (Aponte et al....

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  • ...Since then, hM3Dq has been widely used to enhance neuronal firing, and I here cite only representative examples in which feeding (Krashes et al., 2011; Atasoy et al., 2012), energy expenditure (Kong et al....

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  • ...Based on many reports, CNO appears to be pharmacologically and behaviorally inert in mice (Alexander et al., 2009; Krashes et al., 2011; Farrell et al., 2013; Guettier et al., 2009; Urban et al., 2015; Zhu et al., 2014) and rats (Ferguson et al., 2011, 2013) when administered at the recommended…...

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  • ...This phenomenon might explain why no significant desensitization was seen when DREADDs were virally or transgenically expressed (Alexander et al., 2009; Krashes et al., 2011) Another conceptual issue specific to DREADD technology relates to whether the effects observed regarding neuronal output and behavior occur due to canonical or non-canonical GPCR signaling....

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Journal Article•DOI•
Deconstruction of a neural circuit for hunger

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Deniz Atasoy1, J. Nicholas Betley1, Helen H. Su1, Scott M. Sternson1•
Howard Hughes Medical Institute1
09 Aug 2012-Nature
TL;DR: It is shown that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding, revealing a new neural circuit that regulates hunger state and pathways associated with overeating disorders.
Abstract: Hunger is a complex behavioural state that elicits intense food seeking and consumption. These behaviours are rapidly recapitulated by activation of starvation-sensitive AGRP neurons, which present an entry point for reverse-engineering neural circuits for hunger. Here we mapped synaptic interactions of AGRP neurons with multiple cell populations in mice and probed the contribution of these distinct circuits to feeding behaviour using optogenetic and pharmacogenetic techniques. An inhibitory circuit with paraventricular hypothalamus (PVH) neurons substantially accounted for acute AGRP neuron-evoked eating, whereas two other prominent circuits were insufficient. Within the PVH, we found that AGRP neurons target and inhibit oxytocin neurons, a small population that is selectively lost in Prader-Willi syndrome, a condition involving insatiable hunger. By developing strategies for evaluating molecularly defined circuits, we show that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding. These experiments reveal a new neural circuit that regulates hunger state and pathways associated with overeating disorders.

775 citations

Additional excerpts

  • ...10 pA (6) (11) (5) (5) (7) (5) (11) (5) (5) (7)...

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Journal Article•DOI•
A molecular census of arcuate hypothalamus and median eminence cell types

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John N. Campbell1, Evan Z. Macosko2, Henning Fenselau1, Tune H. Pers3, Tune H. Pers4, Anna Lyubetskaya1, Danielle Tenen1, Melissa Goldman5, Melissa Goldman2, Anne M.J. Verstegen1, Jon M. Resch1, Steven A. McCarroll, Evan D. Rosen1, Evan D. Rosen5, Bradford B. Lowell1, Bradford B. Lowell2, Linus T.-Y. Tsai1 •
Beth Israel Deaconess Medical Center1, Harvard University2, Statens Serum Institut3, University of Copenhagen4, Broad Institute5
01 Mar 2017-Nature Neuroscience
TL;DR: Drop-seq is extended to detect dynamic expression changes across relevant physiological perturbations, revealing cell type–specific responses to energy status, including distinct responses in AgRP and POMC neuron subtypes.
Abstract: The hypothalamic arcuate-median eminence complex (Arc-ME) controls energy balance, fertility and growth through molecularly distinct cell types, many of which remain unknown. To catalog cell types in an unbiased way, we profiled gene expression in 20,921 individual cells in and around the adult mouse Arc-ME using Drop-seq. We identify 50 transcriptionally distinct Arc-ME cell populations, including a rare tanycyte population at the Arc-ME diffusion barrier, a new leptin-sensing neuron population, multiple agouti-related peptide (AgRP) and pro-opiomelanocortin (POMC) subtypes, and an orexigenic somatostatin neuron population. We extended Drop-seq to detect dynamic expression changes across relevant physiological perturbations, revealing cell type-specific responses to energy status, including distinct responses in AgRP and POMC neuron subtypes. Finally, integrating our data with human genome-wide association study data implicates two previously unknown neuron populations in the genetic control of obesity. This resource will accelerate biological discovery by providing insights into molecular and cell type diversity from which function can be inferred.

582 citations

Journal Article•DOI•
Neuropeptide transmission in brain circuits

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Anthony N. van den Pol1•
Yale University1
04 Oct 2012-Neuron
TL;DR: In this article, the authors review converging data revealing a complex interaction between slow-acting neuromodulator peptides and fast-acting amino acid transmitters in the control of energy homeostasis, drug addiction, mood and motivation, sleep-wake states, and neuroendocrine regulation.

557 citations

Additional excerpts

  • ...Selective activation of the NPY/AgRP neuron with DREADD (designer receptors exclusively activated by designer drugs; Rogan and Roth, 2011) receptors increased feeding and reduced energy expenditure (Krashes et al., 2011)....

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References
More filters
Journal Article•DOI•
Driving fast-spiking cells induces gamma rhythm and controls sensory responses

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Jessica A. Cardin1, Marie Carlén2, Marie Carlén3, Konstantinos Meletis2, Konstantinos Meletis3, Ulf Knoblich1, Feng Zhang4, Karl Deisseroth4, Li-Huei Tsai5, Li-Huei Tsai3, Li-Huei Tsai2, Christopher I. Moore1 •
McGovern Institute for Brain Research1, Massachusetts Institute of Technology2, Picower Institute for Learning and Memory3, Stanford University4, Howard Hughes Medical Institute5
04 Jun 2009-Nature
TL;DR: The timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses and provided the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.
Abstract: Corticalgammaoscillations(20280Hz)predictincreasesinfocusedattention,andfailureingammaregulationisahallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons atvariedfrequencies (82200Hz) selectivelyamplifies gamma oscillations. Incontrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data directly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.

2,453 citations

Journal Article•DOI•
Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein

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Michael Martin Ollmann1, Brent D. Wilson1, Brent D. Wilson2, Ying-kui Yang1, Ying-kui Yang2, Julie A. Kerns1, Julie A. Kerns2, Yanru Chen2, Yanru Chen1, Ira Gantz2, Ira Gantz1, Gregory S. Barsh2, Gregory S. Barsh1 •
Stanford University1, University of Michigan2
03 Oct 1997-Science
TL;DR: Recombinant Agouti-related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation and is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling.
Abstract: Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice. Recombinant Agouti-related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation. Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation. Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling.

1,844 citations

"Rapid, reversible activation of AgR..." refers background in this paper

  • ...Overexpression of AgRP in transgenic mice produces obesity, and central administration of the orexigenic peptides, AgRP or NPY, causes hyperphagia (2, 3)....

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Journal Article•DOI•
Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand

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Blaine N. Armbruster1, Xiang Li1, Mark Henry Pausch, Stefan Herlitze1, Bryan L. Roth •
Case Western Reserve University1
20 Mar 2007-Proceedings of the National Academy of Sciences of the United States of America
TL;DR: A facile approach for designing families of GPCRs with engineered ligand specificities will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo.
Abstract: We evolved muscarinic receptors in yeast to generate a family of G protein-coupled receptors (GPCRs) that are activated solely by a pharmacologically inert drug-like and bioavailable compound (clozapine-N-oxide) Subsequent screening in human cell lines facilitated the creation of a family of muscarinic acetylcholine GPCRs suitable for in vitro and in situ studies We subsequently created lines of telomerase-immortalized human pulmonary artery smooth muscle cells stably expressing all five family members and found that each one faithfully recapitulated the signaling phenotype of the parent receptor We also expressed a Gi-coupled designer receptor in hippocampal neurons (hM4D) and demonstrated its ability to induce membrane hyperpolarization and neuronal silencing We have thus devised a facile approach for designing families of GPCRs with engineered ligand specificities Such reverse-engineered GPCRs will prove to be powerful tools for selectively modulating signal-transduction pathways in vitro and in vivo

1,696 citations

"Rapid, reversible activation of AgR..." refers methods in this paper

  • ...To further address whether these same neurons are required for feeding behavior, we used an identical viral approach in which we subsequently expressed the Gi/o-coupled inhibitory DREADD, designated “hM4Di”, in AgRP neurons (10, 11, 14)....

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Journal Article•DOI•
The need to feed: Homeostatic and hedonic control of eating

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Clifford B. Saper1, Thomas C. Chou1, Joel K. Elmquist1•
Beth Israel Deaconess Medical Center1
10 Oct 2002-Neuron
TL;DR: The role played in homeostatic regulation of feeding by systemic mediators such as leptin and ghrelin are examined, which act on brain systems utilizing neuropeptide Y, agouti-related peptide, melanocortins, orexins, and melanin concentrating hormone, among other mediators.

1,095 citations

"Rapid, reversible activation of AgR..." refers background in this paper

  • ...Through neuroscience research, critical contributions can be made in developing an understanding of the mechanisms underlying this problem, ultimately leading to treatment of this escalating disorder (1)....

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Journal Article•DOI•
Divergence of Melanocortin Pathways in the Control of Food Intake and Energy Expenditure

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Nina Balthasar1, Louise Torp Dalgaard1, Charlotte E. Lee1, Jia Yu1, Hisayuki Funahashi1, Todd D. Williams1, Manuel A. R. Ferreira1, Vinsee Tang1, Robert A. McGovern1, Christopher D. Kenny1, Lauryn M. Christiansen1, Elizabeth Edelstein1, Brian Choi1, Olivier Boss1, Carl J. Aschkenasi1, Chen-Yu Zhang1, Kathleen G. Mountjoy2, Toshiro Kishi1, Toshiro Kishi3, Joel K. Elmquist4, Bradford B. Lowell1 •
Harvard University1, Health Science University2, Shimane University3, Beth Israel Deaconess Medical Center4
04 Nov 2005-Cell
TL;DR: It is demonstrated thatMC4Rs in the PVH and/or the amygdala control food intake but that MC4Rs elsewhere control energy expenditure, and association of food intake and energy expenditure reveals unexpected divergence in melanocortin pathways controlling energy balance.

1,002 citations

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Trending Questions (1)
How do you stop Agrp neurons?

Together, these findings demonstrate that AgRP neuron activity is both necessary and sufficient for feeding.

See answers from 2 other papers