AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training

Howard Hughes Medical Institute, Janelia Farm Research Campus, Ashburn, Virginia, USA.
Nature Neuroscience (Impact Factor: 16.1). 03/2011; 14(3):351-5. DOI: 10.1038/nn.2739
Source: PubMed


Two intermingled hypothalamic neuron populations specified by expression of agouti-related peptide (AGRP) or pro-opiomelanocortin (POMC) positively and negatively influence feeding behavior, respectively, possibly by reciprocally regulating downstream melanocortin receptors. However, the sufficiency of these neurons to control behavior and the relationship of their activity to the magnitude and dynamics of feeding are unknown. To measure this, we used channelrhodopsin-2 for cell type-specific photostimulation. Activation of only 800 AGRP neurons in mice evoked voracious feeding within minutes. The behavioral response increased with photoexcitable neuron number, photostimulation frequency and stimulus duration. Conversely, POMC neuron stimulation reduced food intake and body weight, which required melanocortin receptor signaling. However, AGRP neuron-mediated feeding was not dependent on suppressing this melanocortin pathway, indicating that AGRP neurons directly engage feeding circuits. Furthermore, feeding was evoked selectively over drinking without training or prior photostimulus exposure, which suggests that AGRP neurons serve a dedicated role coordinating this complex behavior.

Download full-text


Available from: Scott M Sternson,
    • "Here, we show that, in contrast, P2Y6 directly activates AgRP neurons in the ARH to potently promote feeding, while it only has minor effects on the activation of anorexigenic POMC neurons. This notion is consistent with the robust activation of feeding upon optogenetic or pharmacogenetic activation of AgRP neurons (Aponte et al., 2011; Krashes et al., 2011) and their previously defined crucial role for the maintenance of feeding, as evidenced by toxin-mediated ablation of these cells in adult mice (Gropp et al., 2005; Luquet et al., 2005). Besides our demonstration that AgRP neurons express P2Y6 and that AgRP neuron activity is required to promote feeding in response to centrally applied UDP, we reveal that UDP triggers pERK phosphorylation and increased action potential firing in a substantial proportion of AgRP neurons. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Activation of orexigenic AgRP-expressing neurons in the arcuate nucleus of the hypothalamus potently promotes feeding, thus defining new regulators of AgRP neuron activity could uncover potential novel targets for obesity treatment. Here, we demonstrate that AgRP neurons express the purinergic receptor 6 (P2Y6), which is activated by uridine-diphosphate (UDP). In vivo, UDP induces ERK phosphorylation and cFos expression in AgRP neurons and promotes action potential firing of these neurons in brain slice recordings. Consequently, central application of UDP promotes feeding, and this response is abrogated upon pharmacologic or genetic inhibition of P2Y6 as well as upon pharmacogenetic inhibition of AgRP neuron activity. In obese animals, hypothalamic UDP content is elevated as a consequence of increased circulating uridine concentrations. Collectively, these experiments reveal a potential regulatory pathway in obesity, where peripheral uridine increases hypothalamic UDP concentrations, which in turn can promote feeding via PY6-dependent activation of AgRP neurons.
    Cell 09/2015; 162(6):1404-1417. DOI:10.1016/j.cell.2015.08.032 · 32.24 Impact Factor
  • Source
    • "Recent advances in techniques that permit the reversible and temporal manipulation of neuronal activity by cell type-specificity allow the researcher to unravel the interaction between the neuromediators secreted by AgRP neurons. By using an activated cation channel rhodopsin-2 by photostimulation (Aponte et al., 2011), as well as by using technology involving activation of designer receptors by designer drugs (DREADD) (Krashes et al., 2013); it was demonstrated that acute activation of AgRP neurons rapidly induces food seeking and consumption within minutes of AgRP neuronal activation. Importantly, these studies show a temporal dissociation between the effect of GABA, NPY and AgRP peptides on regulating of food intake suggesting that GABA and NPY are both required for acute feeding whereas AgRP is solely involved in longterm regulation of feeding behavior through its interaction with melanocortin receptors (Atasoy et al., 2012; Krashes et al., 2013). "
    [Show abstract] [Hide abstract]
    ABSTRACT: The incidence of obesity and its related disorders are increasing at a rate of pandemic proportions. Understanding the mechanisms behind the maintenance of energy balance is fundamental in developing treatments for clinical syndromes including obesity and diabetes. A neural network located in the the nucleus of the solitary tract-area postrema complex in the hindbrain and the hypothalamus in the forebrain has long been implicated in the control of energy balance. In the hypothalamus this central neuronal network consists of small populations of nuclei with distinct functions such as the arcuate nucleus (ARH), the paraventricular nuclei of the hypothalamus (PVH), the dorsomedial (DMH), the ventromedial (VMH) and the lateral hypothalamus (LH). These hypothalamic areas form interconnected neuronal circuits that respond to fluctuations in energy status by altering the expression of neuropeptides, leading to changes in energy intake and expenditure. Regulation of these hypothalamic nuclei involves the actions of orexigenic peptides (ie ghrelin), which act to stimulate energy intake and decrease energy expenditure, and anorexigenic peptides (ie. leptin and insulin), which act to reduce energy intake and stimulate energy expenditure. Here we review the role of the ARH, DMH and PVH in the control of energy homeostasis and how recent advances in research technologies (Cre-loxP technology, optogenetics and pharmacogenetics) have shed light on the role of these hypothalamic nuclei in the control of energy balance. Such novel findings include the implication of ARH POMC and AgRP neurons in the browning of white adipose tissue to regulate energy expenditure as well as the likely existence of divergent hypothalamic pathways in the DMH and PVH in the control of food intake and energy expenditure. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Molecular and Cellular Endocrinology 08/2015; DOI:10.1016/j.mce.2015.08.022 · 4.41 Impact Factor
  • Source
    • "Understanding the net contribution of homeostatic energy-driven and non-homeostatic reward-driven feeding has become critical and requires a deeper understanding of the neuronal mechanism by which energy needs and reward participate in food intake. AgRP neurons represent a critical component of the homeostatic circuitry that respond to decreased nutrient availability by engaging the full sequence of feeding behaviors (Aponte et al., 2011; Carter et al., 2013; Cowley et al., 1999, 2003; Krashes et al., 2011). Furthermore, ablation of AgRP neurons in adult mice results in profound anorexia (Bewick et al., 2005; Gropp et al., 2005; Luquet et al., 2005; Xu et al., 2005). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Feeding behavior is exquisitely regulated by homeostatic and hedonic neural substrates that integrate energy demand as well as the reinforcing and rewarding aspects of food. Understanding the net contribution of homeostatic and reward-driven feeding has become critical because of the ubiquitous source of energy-dense foods and the consequent obesity epidemic. Hypothalamic agouti-related peptide-secreting neurons (AgRP neurons) provide the primary orexigenic drive of homeostatic feeding. Using models of neuronal inhibition or ablation, we demonstrate that the feeding response to a fast ghrelin or serotonin receptor agonist relies on AgRP neurons. However, when palatable food is provided, AgRP neurons are dispensable for an appropriate feeding response. In addition, AgRP-ablated mice present exacerbated stress-induced anorexia and palatable food intake-a hallmark of comfort feeding. These results suggest that, when AgRP neuron activity is impaired, neural circuits sensitive to emotion and stress are engaged and modulated by food palatability and dopamine signaling. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 08/2015; 22(4). DOI:10.1016/j.cmet.2015.07.011 · 17.57 Impact Factor
Show more