Rapid versus Delayed Stimulation of Feeding by the Endogenously Released AgRP Neuron Mediators GABA, NPY, and AgRP

doi:10.1016/J.CMET.2013.09.009

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Rapid versus Delayed Stimulation of Feeding by the Endogenously Released AgRP Neuron Mediators GABA, NPY, and AgRP

Journal Article•DOI•

Rapid versus Delayed Stimulation of Feeding by the Endogenously Released AgRP Neuron Mediators GABA, NPY, and AgRP

Michael J. Krashes¹, Bhavik P. Shah¹, Shuichi Koda¹, Bradford B. Lowell¹•Institutions (1)

Beth Israel Deaconess Medical Center¹

01 Oct 2013-Cell Metabolism (NIH Public Access)-Vol. 18, Iss: 4, pp 588-595

TL;DR: It is found that either GABA or NPY is required for the rapid stimulation of feeding, and the neuropeptide AgRP, through action on MC4 receptors, is sufficient to induce feeding over a delayed yet prolonged period.

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About: This article is published in Cell Metabolism.The article was published on 2013-10-01 and is currently open access. It has received 282 citations till now. The article focuses on the topics: Neuropeptide Y receptor & Neuropeptide.

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Journal Article•DOI•

DREADDs for Neuroscientists.

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Bryan L. Roth¹•Institutions (1)

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.

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1,145 citations

Cites background from "Rapid versus Delayed Stimulation of..."

...Given the long residence time of CNO, it is not surprising that the in vivo effects of CNO-mediated activation of hM3Dq can be both robust and prolonged (Alexander et al., 2009; Krashes et al., 2013)....
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Journal Article•DOI•

Neurobiology of food intake in health and disease.

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Gregory J. Morton¹, Thomas H. Meek¹, Michael W. Schwartz¹•Institutions (1)

University of Washington¹

01 Jun 2014-Nature Reviews Neuroscience

TL;DR: How the interplay between homeostatic and emergency feeding circuits influences the biologically defended level of body weight under physiological and pathophysiological conditions is highlighted.

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Abstract: Under normal conditions, food intake and energy expenditure are balanced by a homeostatic system that maintains stability of body fat content over time. However, this homeostatic system can be overridden by the activation of 'emergency response circuits' that mediate feeding responses to emergent or stressful stimuli. Inhibition of these circuits is therefore permissive for normal energy homeostasis to occur, and their chronic activation can cause profound, even life-threatening, changes in body fat mass. This Review highlights how the interplay between homeostatic and emergency feeding circuits influences the biologically defended level of body weight under physiological and pathophysiological conditions.

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544 citations

Journal Article•DOI•

DREADDs (Designer Receptors Exclusively Activated by Designer Drugs): Chemogenetic Tools with Therapeutic Utility

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Daniel J. Urban¹, Bryan L. Roth¹•Institutions (1)

University of North Carolina at Chapel Hill¹

06 Jan 2015-Annual Review of Pharmacology and Toxicology

TL;DR: A specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): DREADDs (designer receptors exclusively activated by designer drugs), which is shown to be used ubiquitously to modulate GPCR activity noninvasively in vivo.

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Abstract: In the past decade, emerging synthetic biology technologies such as chemogenetics have dramatically transformed how pharmacologists and systems biologists deconstruct the involvement of G protein-coupled receptors (GPCRs) in a myriad of physiological and translational settings. Here we highlight a specific chemogenetic application that extends the utility of the concept of RASSLs (receptors activated solely by synthetic ligands): We have dubbed it DREADDs (designer receptors exclusively activated by designer drugs). As we show in this review, DREADDs are now used ubiquitously to modulate GPCR activity noninvasively in vivo. Results from these studies have directly implicated GPCR signaling in a large number of therapeutically relevant contexts. We also highlight recent applications of DREADD technology that have illuminated GPCR signaling processes that control pathways relevant to the treatment of eating disorders, obesity, and obesity-associated metabolic abnormalities. Additionally, we provide an overview of the potential utility of chemogenetic technologies for transformative therapeutics.

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532 citations

Journal Article•DOI•

An Excitatory Paraventricular Nucleus to AgRP Neuron Circuit That Drives Hunger

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Michael J. Krashes¹, Michael J. Krashes², Bhavik P. Shah¹, Bhavik P. Shah², Joseph C. Madara², David P. Olson², David P. Olson¹, David E. Strochlic³, Alastair S. Garfield², Linh Vong², Linh Vong¹, Hongjuan Pei⁴, Mitsuko Watabe-Uchida³, Naoshige Uchida³, Stephen D. Liberles³, Bradford B. Lowell² - Show less +12 more•Institutions (4)

National Institutes of Health¹, Beth Israel Deaconess Medical Center², Harvard University³, University of Michigan⁴

13 Mar 2014-Nature

TL;DR: Strong excitatory drive is discovered that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP)

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Abstract: Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre-recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase-activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric-deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated.

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497 citations

Journal Article•DOI•

Neurons for hunger and thirst transmit a negative-valence teaching signal

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J. Nicholas Betley¹, Shengjin Xu¹, Zhen Fang Huang Cao¹, Rong Gong¹, Christopher J. Magnus¹, Yang Yu¹, Scott M. Sternson¹ - Show less +3 more•Institutions (1)

Howard Hughes Medical Institute¹

14 May 2015-Nature

TL;DR: It is found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal, and these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-Valence signals during restoration of homeostasis.

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Abstract: Homeostasis is a biological principle for regulation of essential physiological parameters within a set range. Behavioural responses due to deviation from homeostasis are critical for survival, but motivational processes engaged by physiological need states are incompletely understood. We examined motivational characteristics of two separate neuron populations that regulate energy and fluid homeostasis by using cell-type-specific activity manipulations in mice. We found that starvation-sensitive AGRP neurons exhibit properties consistent with a negative-valence teaching signal. Mice avoided activation of AGRP neurons, indicating that AGRP neuron activity has negative valence. AGRP neuron inhibition conditioned preference for flavours and places. Correspondingly, deep-brain calcium imaging revealed that AGRP neuron activity rapidly reduced in response to food-related cues. Complementary experiments activating thirst-promoting neurons also conditioned avoidance. Therefore, these need-sensing neurons condition preference for environmental cues associated with nutrient or water ingestion, which is learned through reduction of negative-valence signals during restoration of homeostasis.

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493 citations

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References

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Journal Article•DOI•

Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus

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Michael A. Cowley¹, James L. Smart¹, Marcelo Rubinstein², Marcelo G. Cerdán², Sabrina Diano, Tamas L. Horvath³, Roger D. Cone¹, Malcolm J. Low¹ - Show less +4 more•Institutions (3)

Oregon Health & Science University¹, University of Buenos Aires², Yale University³

24 May 2001-Nature

TL;DR: An integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus is proposed and it is shown that melanocortin peptides have an autoinhibitory effect on this circuit.

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Abstract: The administration of leptin to leptin-deficient humans, and the analogous Lepob/Lepob mice, effectively reduces hyperphagia and obesity. But common obesity is associated with elevated leptin, which suggests that obese humans are resistant to this adipocyte hormone. In addition to regulating long-term energy balance, leptin also rapidly affects neuronal activity. Proopiomelanocortin (POMC) and neuropeptide-Y types of neurons in the arcuate nucleus of the hypothalamus are both principal sites of leptin receptor expression and the source of potent neuropeptide modulators, melanocortins and neuropeptide Y, which exert opposing effects on feeding and metabolism. These neurons are therefore ideal for characterizing leptin action and the mechanism of leptin resistance; however, their diffuse distribution makes them difficult to study. Here we report electrophysiological recordings on POMC neurons, which we identified by targeted expression of green fluorescent protein in transgenic mice. Leptin increases the frequency of action potentials in the anorexigenic POMC neurons by two mechanisms: depolarization through a nonspecific cation channel; and reduced inhibition by local orexigenic neuropeptide-Y/GABA (gamma-aminobutyric acid) neurons. Furthermore, we show that melanocortin peptides have an autoinhibitory effect on this circuit. On the basis of our results, we propose an integrated model of leptin action and neuronal architecture in the arcuate nucleus of the hypothalamus.

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2,193 citations

"Rapid versus Delayed Stimulation of..." refers background in this paper

...Data shown are from male mice (error bars indicate mean ± SEM, n = 9 AgRP-ires-Cre mice; n = 9 AgRP-ires-Cre; Vgatflox/flox; Npy / mice; *p < 0.05). these boutons formed synapses onto POMC perikarya (Cowley et al., 2001)....
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...these boutons formed synapses onto POMC perikarya (Cowley et al., 2001)....
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...Interestingly, acute brain slice electrophysiology has demonstrated the fast temporal dynamics of NPY application onto downstream POMC neurons (Cowley et al., 2001)....
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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 Yang², Ying-kui Yang¹, Julie A. Kerns², Julie A. Kerns¹, Yanru Chen², Yanru Chen¹, Ira Gantz¹, Ira Gantz², Gregory S. Barsh², Gregory S. Barsh¹ - Show less +9 more•Institutions (2)

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.

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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.

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1,844 citations

"Rapid versus Delayed Stimulation of..." refers background in this paper

...Moreover, the genetic overexpression of the AgRP gene encoding the neuropeptide, which acts as an antagonist and inverse agonist on downstream melanocortin 4 receptors (MC4R), promotes food intake (Ollmann et al., 1997)....
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Journal Article•DOI•

Neuropeptide y and human pancreatic polypeptide stimulate feeding behavior in rats

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John T. Clark, Pushpa S. Kalra, William R. Crowley, Satya P. Kalra

01 Jul 1984-Endocrinology

TL;DR: Findings imply that neuropeptide Y, or a closely related pancreatic polypeptides-like neuropePTide, plays an important role in neural regulation of feeding behavior.

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Abstract: Observations that a pancreatic polypeptide-like substance, possibly neuropeptide Y, is present in hypothalamic areas and may coexist with catecholamines prompted evaluation of its role in controlling feeding behavior. Intracerebroventricular administration of 2 or 10 micrograms of human pancreatic polypeptide to ovariectomized rats pretreated with estradiol benzoate plus progesterone significantly increased the number of animals feeding, and total food intake in tests conducted during the light phase of the day. Administration of neuropeptide Y, 2 or 10 micrograms, induced feeding in all rats, and food intake was 3 times greater than that observed after human pancreatic polypeptide injection. These findings imply that neuropeptide Y, or a closely related pancreatic polypeptide-like neuropeptide, plays an important role in neural regulation of feeding behavior.

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1,290 citations

"Rapid versus Delayed Stimulation of..." refers background in this paper

...The pharmacological administration of either NPY or AgRP into the hypothalamus induces a robust hyperphagic response in rodents (Clark et al., 1984; Rossi et al., 1998; Semjonous et al., 2009) with distinct temporal dynamics; NPY results in immediate feeding, whereas AgRP increases food intake over a delayed, longer time scale (Semjonous et al....
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...The pharmacological administration of either NPY or AgRP into the hypothalamus induces a robust hyperphagic response in rodents (Clark et al., 1984; Rossi et al., 1998; Semjonous et al., 2009) with distinct temporal dynamics; NPY results in immediate feeding, whereas AgRP increases food intake over…...
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Journal Article•DOI•

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

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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 - Show less +5 more•Institutions (3)

Beth Israel Deaconess Medical Center¹, Harvard University², University of North Carolina at Chapel Hill³

01 Apr 2011-Journal of Clinical Investigation

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.

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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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1,170 citations

"Rapid versus Delayed Stimulation of..." refers background or methods in this paper

...3 mg/kg) administration, resulted in voracious feeding in AgRP-ires-Cre mice over the first 2 hr (Figures 1A and S1A) and across a 24 hr window (Figures 1B and S1B) in comparison to the samemice after a saline injection (Krashes et al., 2011) but failed to evoke food intake in triple KO mice, demonstrating that the release of either GABA, NPY, and/or AgRP action onto MC4Rs is required for increases in food intake after direct AgRP neuronal stimulation (a post hoc Tukey test showed that CNO-treated AgRP-ires-Cre mice exhibited significantly...
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...…mice over the first 2 hr (Figures 1A and S1A) and across a 24 hr window (Figures 1B and S1B) in comparison to the samemice after a saline injection (Krashes et al., 2011) but failed to evoke food intake in triple KO mice, demonstrating that the release of either GABA, NPY, and/or AgRP action onto…...
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...These episodes are characterized by mice approaching the food hopper, initiating feeding behavior, and continuing to visibly eat for an extended period of time exceeding 3 min (Krashes et al., 2011)....
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...DREADD-Mediated AgRP Stimulation in Triple KO Mice Abrogates Feeding Response As proof of principle, we targeted a Cre-dependent adeno-associated virus (AAV) expressing the hM3Dq excitatory DREADD (Krashes et al., 2011), specifically to AgRP neurons with either AgRP-ires-Cre control or AgRP-ires-Cre; Mc4r / ; Vgat; Npy / triple knockout (KO) mice lacking GABA release from AgRP neurons as well as ubiquitous deletion of NPY and MC4R, the downstream target of the AgRP neuropeptide (Balthasar et al....
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...…inconsistencies, we employed stimulatory designer receptors exclusively activated by designer drugs (DREADD) technology (Alexander et al., 2009; Krashes et al., 2011) in order to acutely and explicitly activate AgRP neurons in genetic mouse models that have had the release of GABA, NPY, or…...
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Journal Article•DOI•

Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y

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Jay C. Erickson¹, Kathy E. Clegg¹, Richard D. Palmiter¹•Institutions (1)

University of Washington¹

30 May 1996-Nature

TL;DR: It is reported here that mice deficient for NPY have normal food intake and body weight, and become hyperphagic following food deprivation, and mutants are more susceptible to seizures induced by a GABA (γ-aminobutyric acid) antagonist when treated with recombinant leptin.

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Abstract: NEUROPEPTIDE Y (NPY), a 36-amino-acid transmitter distributed throughout the nervous system1,2, is thought to function as a central stimulator of feeding behaviour1–4. NPY has also been implicated in the modulation of mood5, cerebrocortical excitability6, hypothalamic–pituitary signalling7, cardiovascular physiology1,8 and sympathetic function9,10. However, the biological significance of NPY has been difficult to establish owing to a lack of pharmacological antagonists. We report here that mice deficient for NPY have normal food intake and body weight, and become hyperphagic following food deprivation. Mutant mice decrease their food intake and lose weight, initially to a greater extent than controls, when treated with recombinant leptin. Occasional, mild seizures occur in NPY-deficient mice and mutants are more susceptible to seizures induced by a GABA (γ-aminobutyric acid) antagonist. These results indicate that NPY is not essential for certain feeding responses or leptin actions but is an important modulator of excitability in the central nervous system.

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1,036 citations

"Rapid versus Delayed Stimulation of..." refers background in this paper

...…or AgRP-ires-Cre; Mc4r / ; Vgatflox/flox; Npy / triple knockout (KO) mice lacking GABA release from AgRP neurons as well as ubiquitous deletion of NPY and MC4R, the downstream target of the AgRP neuropeptide (Balthasar et al., 2005; Erickson et al., 1996; Marsh et al., 1999b; Tong et al., 2008)....
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...Despite these findings, the targeted deletion of Agrp, Npy, and/or Slc32a1 (vesicular GABA transporter [VGAT]; required for GABA release) all have minimal effects on feeding (Erickson et al., 1996; Qian et al., 2002; Tong et al., 2008)....
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...Metabolism 18, 588–595, October 1, 2013 ª2013 Elsevier Inc. 593 AgRP-ires-Cre (Tong et al., 2008), Vgatflox/flox (Tong et al., 2008),Npy / (Erickson et al., 1996), and Mc4r / (Balthasar et al., 2005) mice were previously described....
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