The hormonal signature of energy deficit: Increasing the value of food reward.

Energy deficit is characterised by high ghrelin levels, and low leptin and insulin levels and we suggest that this provides a metabolic signature sensed by the brain to increase motivated behaviour to obtain food. We believe that the hormonal profile of negative energy balance serves to increase the incentive salience (or the value) of a food reinforcer, which in turn leads to increased motivation to obtain this reinforcer. These processes are mediated by a number of alterations in the mesolimbic dopamine system which serves to increase dopamine availability in the forebrain during energy deficit. The currently available evidence suggests that changes in motivational state, rather than hedonic enjoyment of taste, are primarily affected by reduced energy availability. This review aims to clarify the term 'reward' in the metabolic literature and promote more focused discussion in future studies.

[1]  J. Elmquist,et al.  Functional implications of limited leptin receptor and ghrelin receptor coexpression in the brain , 2012, The Journal of comparative neurology.

[2]  R. Cone,et al.  Altered expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation. , 1999, Endocrinology.

[3]  C. Saper,et al.  Expression of ghrelin receptor mRNA in the rat and the mouse brain , 2006, The Journal of comparative neurology.

[4]  Kyle S. Smith,et al.  Hedonic and motivational roles of opioids in food reward: Implications for overeating disorders , 2010, Pharmacology Biochemistry and Behavior.

[5]  F. Gonon,et al.  Increased rewarding properties of morphine in dopamine‐transporter knockout mice , 2000, The European journal of neuroscience.

[6]  K. Berridge.  The debate over dopamine’s role in reward: the case for incentive salience , 2007, Psychopharmacology.

[7]  M. Dietrich,et al.  AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors , 2012, Nature Neuroscience.

[8]  G. Bernardi,et al.  Pharmacological identification of the K+ currents mediating the hypoglycemic hyperpolarization of rat midbrain dopaminergic neurones , 2000, Neuropharmacology.

[9]  H. Schmidt,et al.  Amylin Receptor Signaling in the Ventral Tegmental Area is Physiologically Relevant for the Control of Food Intake , 2013, Neuropsychopharmacology.

[10]  Maria Pia Fantini,et al.  Does Pet Ownership in Infancy Lead to Asthma or Allergy at School Age? Pooled Analysis of Individual Participant Data from 11 European Birth Cohorts , 2012, PloS one.

[11]  Simon Hess,et al.  Role for insulin signaling in catecholaminergic neurons in control of energy homeostasis. , 2011, Cell metabolism.

[12]  S. Woods,et al.  Ghrelin Enhances Olfactory Sensitivity and Exploratory Sniffing in Rodents and Humans , 2011, The Journal of Neuroscience.

[13]  Z. Andrews.  Central mechanisms involved in the orexigenic actions of ghrelin , 2011, Peptides.

[14]  R. Palmiter,et al.  Distinguishing whether dopamine regulates liking, wanting, and/or learning about rewards. , 2005, Behavioral neuroscience.

[15]  S. B. Evans,et al.  Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat , 2003, Brain Research.

[16]  S. Iversen,et al.  Increased food intake after opioid microinjections into nucleus accumbens and ventral tegmental area of rat , 1986, Brain Research.

[17]  K. Berridge,et al.  Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue‐triggered ‘wanting’ for reward: entire core and medial shell mapped as substrates for PIT enhancement , 2013, The European journal of neuroscience.

[18]  Roy G. Smith,et al.  Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. , 1997, Brain research. Molecular brain research.

[19]  D. Lodge,et al.  Selective Deletion of the Leptin Receptor in Dopamine Neurons Produces Anxiogenic-like Behavior and Increases Dopaminergic Activity in Amygdala , 2011, Molecular Psychiatry.

[20]  Xiao-Bing Gao,et al.  Leptin Receptor Signaling in Midbrain Dopamine Neurons Regulates Feeding , 2006, Neuron.

[21]  D. Figlewicz,et al.  Food Deprivation Decreases mRNA and Activity of the Rat Dopamine Transporter , 1998, Neuroendocrinology.

[22]  S. Haber,et al.  Opioid modulation of taste hedonics within the ventral striatum , 2002, Physiology & Behavior.

[23]  K. Berridge,et al.  Hedonic Hot Spot in Nucleus Accumbens Shell: Where Do μ-Opioids Cause Increased Hedonic Impact of Sweetness? , 2005, The Journal of Neuroscience.

[24]  Linh Vong,et al.  Leptin Action on GABAergic Neurons Prevents Obesity and Reduces Inhibitory Tone to POMC Neurons , 2011, Neuron.

[25]  S. Cabib,et al.  PSYCHOPHARMACOLOGY OF DOPAMINE: THE CONTRIBUTION OF COMPARATIVE STUDIES IN INBRED STRAINS OF MICE , 1997, Progress in Neurobiology.

[26]  Z. Andrews,et al.  Metabolic Status Regulates Ghrelin Function on Energy Homeostasis , 2010, Neuroendocrinology.

[27]  S. Woods,et al.  Combined Blockade of Both μ- and κ-Opioid Receptors Prevents the Acute Orexigenic Action of Agouti-Related Protein , 2002 .

[28]  R. Wise,et al.  Ventral tegmental injections of morphine but not U-50,488H enhance feeding in food-deprived rats , 1993, Brain Research.

[29]  Kyle S. Smith,et al.  Endocannabinoid Hedonic Hotspot for Sensory Pleasure: Anandamide in Nucleus Accumbens Shell Enhances ‘Liking’ of a Sweet Reward , 2007, Neuropsychopharmacology.

[30]  A. Levine,et al.  Ghrelin induces feeding in the mesolimbic reward pathway between the ventral tegmental area and the nucleus accumbens , 2005, Peptides.

[31]  R. Palmiter,et al.  NPY/AgRP Neurons Are Essential for Feeding in Adult Mice but Can Be Ablated in Neonates , 2005, Science.

[32]  S. Fulton,et al.  Leptin Regulation of the Mesoaccumbens Dopamine Pathway , 2006, Neuron.

[33]  Michael Esterman,et al.  The Distribution and Mechanism of Action of Ghrelin in the CNS Demonstrates a Novel Hypothalamic Circuit Regulating Energy Homeostasis , 2003, Neuron.

[34]  D. Burdakov,et al.  Physiological Changes in Glucose Differentially Modulate the Excitability of Hypothalamic Melanin-Concentrating Hormone and Orexin Neurons In Situ , 2005, The Journal of Neuroscience.

[35]  H. Berthoud,et al.  The lateral hypothalamus as integrator of metabolic and environmental needs: From electrical self-stimulation to opto-genetics , 2011, Physiology & Behavior.

[36]  Robert C. Thompson,et al.  Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. , 2011, Cell metabolism.

[37]  N. Sousa,et al.  A Trans-Dimensional Approach to the Behavioral Aspects of Depression , 2008, Front. Behav. Neurosci..

[38]  R. Palmiter,et al.  Loss of GABAergic Signaling by AgRP Neurons to the Parabrachial Nucleus Leads to Starvation , 2009, Cell.

[39]  R. Palmiter,et al.  Dopamine is required for hyperphagia in Lepob/ob mice , 2000, Nature Genetics.

[40]  W. Kiess,et al.  Basal and feeding-evoked dopamine release in the rat nucleus accumbens is depressed by leptin. , 2003, European journal of pharmacology.

[41]  Rainer Spanagel,et al.  Opposing tonically active endogenous opioid systems modulate the mesolimbic dopaminergic pathway , 1992 .

[42]  Jon F. Davis,et al.  Leptin Regulates Energy Balance and Motivation Through Action at Distinct Neural Circuits , 2011, Biological Psychiatry.

[43]  Kyle S. Smith,et al.  Dynamic Computation of Incentive Salience: “Wanting” What Was Never “Liked” , 2009, The Journal of Neuroscience.

[44]  S. Woods,et al.  Opioid receptor involvement in the effect of AgRP- (83-132) on food intake and food selection. , 2001, American journal of physiology. Regulatory, integrative and comparative physiology.

[45]  A. Haghparast,et al.  Streptozotocin-induced diabetes affects the development and maintenance of morphine reward in rats , 2013, Neuroscience Letters.

[46]  S. Dickson,et al.  Ghrelin interacts with neuropeptide Y Y1 and opioid receptors to increase food reward. , 2012, Endocrinology.

[47]  M. R. Hayes,et al.  GLP-1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. , 2012, Endocrinology.

[48]  R. Bolles,et al.  Nutritive expectancies mediate cholecystokinin's suppression-of-intake effect. , 1988, Behavioral neuroscience.

[49]  D. Macneil,et al.  Neither Agouti-Related Protein nor Neuropeptide Y Is Critically Required for the Regulation of Energy Homeostasis in Mice , 2002, Molecular and Cellular Biology.

[50]  C. Schwarzer,et al.  Hypothalamic κ-Opioid Receptor Modulates the Orexigenic Effect of Ghrelin , 2013, Neuropsychopharmacology.

[51]  O. Rønnekleiv,et al.  Neurons in the rat arcuate nucleus are hyperpolarized by GABAB and mu-opioid receptor agonists: evidence for convergence at a ligand-gated potassium conductance. , 1991, Neuroendocrinology.

[52]  S. Dickson,et al.  Role of ghrelin in food reward: impact of ghrelin on sucrose self-administration and mesolimbic dopamine and acetylcholine receptor gene expression , 2012, Addiction biology.

[53]  A. Kelley,et al.  Nucleus Accumbens μ-Opioids Regulate Intake of a High-Fat Diet via Activation of a Distributed Brain Network , 2003, The Journal of Neuroscience.

[54]  O. Rønnekleiv,et al.  Opioids Hyperpolarize β-Endorphin Neurons via μ-Receptor Activation of a Potassium Conductance , 1990 .

[55]  B. Simmen,et al.  Relationship between taste thresholds and hunger under debate , 2006, Appetite.

[56]  Kiyoshi Koyano,et al.  Diurnal Variation of Human Sweet Taste Recognition Thresholds Is Correlated With Plasma Leptin Levels , 2008, Diabetes.

[57]  D. Cummings,et al.  Integrative and Translational Physiology : Integrative Aspects of Energy Homeostasis and Metabolic Diseases Ghrelin increases the motivation to eat , but does not alter food palatability , 2012 .

[58]  Hiroshi Yamada,et al.  Hydration level is an internal variable for computing motivation to obtain water rewards in monkeys , 2012, Experimental Brain Research.

[59]  Roy G. Smith,et al.  Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. , 2006, Molecular endocrinology.

[60]  T. Dinan,et al.  Ghrelin at the interface of obesity and reward. , 2013, Vitamins and hormones.

[61]  R. Bolles,et al.  Hunger enhances the expression of calorie- but not taste-mediated conditioned flavor preferences. , 1987, Journal of experimental psychology. Animal behavior processes.

[62]  R. Palmiter,et al.  Feeding behavior in dopamine-deficient mice. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[63]  M. Tschöp,et al.  An anatomic basis for the communication of hypothalamic, cortical and mesolimbic circuitry in the regulation of energy balance , 2009, The European journal of neuroscience.

[64]  T. Horvath,et al.  Central administration of ghrelin and agouti-related protein (83-132) increases food intake and decreases spontaneous locomotor activity in rats. , 2004, Endocrinology.

[65]  M. Low,et al.  Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus , 2001, Nature.

[66]  M. Lutter,et al.  Ghrelin Increases the Rewarding Value of High-Fat Diet in an Orexin-Dependent Manner , 2010, Biological Psychiatry.

[67]  S. B. Evans,et al.  Intraventricular insulin and leptin reverse place preference conditioned with high-fat diet in rats. , 2004, Behavioral neuroscience.

[68]  D. Clegg,et al.  The melanocortin antagonist AgRP (83–132) increases appetitive responding for a fat, but not a carbohydrate, reinforcer , 2008, Pharmacology Biochemistry and Behavior.

[69]  Jovi C. Y. Wong,et al.  Insulin in the ventral tegmental area reduces hedonic feeding and suppresses dopamine concentration via increased reuptake , 2012, The European journal of neuroscience.

[70]  A. Dagher.  Functional brain imaging of appetite , 2012, Trends in Endocrinology & Metabolism.

[71]  D. Figlewicz,et al.  Intraventricular insulin and leptin decrease sucrose self-administration in rats , 2006, Physiology & Behavior.

[72]  J. Salamone,et al.  Dopamine and Food Addiction: Lexicon Badly Needed , 2013, Biological Psychiatry.

[73]  Jon F. Davis,et al.  Central melanocortins modulate mesocorticolimbic activity and food seeking behavior in the rat , 2011, Physiology & Behavior.

[74]  H. Vogel,et al.  Divergent circuitry underlying food reward and intake effects of ghrelin: Dopaminergic VTA-accumbens projection mediates ghrelin's effect on food reward but not food intake , 2013, Neuropharmacology.

[75]  P. Fedorchak,et al.  Caffeine-reinforced conditioned flavor preferences in rats , 2002 .

[76]  P. Abreu,et al.  Increased or decreased locomotor response in rats following repeated administration of apomorphine depends on dosage interval , 2004, Psychopharmacology.

[77]  H. Berthoud,et al.  Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP. , 2002, American journal of physiology. Regulatory, integrative and comparative physiology.

[78]  J. Salamone,et al.  The Mysterious Motivational Functions of Mesolimbic Dopamine , 2012, Neuron.

[79]  R. Spanagel,et al.  REVIEW: Behavioural assessment of drug reinforcement and addictive features in rodents: an overview , 2006, Addiction biology.

[80]  P. Olszewski,et al.  Central ghrelin induces feeding driven by energy needs not by reward , 2007, Neuroreport.

[81]  S. Dickson,et al.  PRECLINICAL STUDY: Ghrelin stimulates locomotor activity and accumbal dopamine‐overflow via central cholinergic systems in mice: implications for its involvement in brain reward , 2006, Addiction biology.

[82]  N. Volkow,et al.  Food restriction markedly increases dopamine D2 receptor (D2R) in a rat model of obesity as assessed with in‐vivo μPET imaging ([11C] raclopride) and in‐vitro ([3H] spiperone) autoradiography , 2008, Synapse.

[83]  Kyle S. Smith,et al.  The Ventral Pallidum and Hedonic Reward: Neurochemical Maps of Sucrose “Liking” and Food Intake , 2005, The Journal of Neuroscience.

[84]  T. Sakurai,et al.  Neurons containing orexin in the lateral hypothalamic area of the adult rat brain are activated by insulin-induced acute hypoglycemia , 1999, Neuroscience Letters.

[85]  Filip Bergquist,et al.  The Glucagon-Like Peptide 1 (GLP-1) Analogue, Exendin-4, Decreases the Rewarding Value of Food: A New Role for Mesolimbic GLP-1 Receptors , 2012, The Journal of Neuroscience.

[86]  H. Münzberg,et al.  Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. , 2009, Cell metabolism.

[87]  B. Messaoudi,et al.  A Physiological Increase of Insulin in the Olfactory Bulb Decreases Detection of a Learned Aversive Odor and Abolishes Food Odor-Induced Sniffing Behavior in Rats , 2012, PloS one.

[88]  Kanji A. Takahashi,et al.  Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/Agouti-related protein neurons. , 2005, Endocrinology.

[89]  B. Roth,et al.  Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. , 2011, The Journal of clinical investigation.

[90]  H. Loh,et al.  Regulation of opioid receptor activities. , 1999, The Journal of pharmacology and experimental therapeutics.

[91]  S. Dickson,et al.  The rat arcuate nucleus integrates peripheral signals provided by leptin, insulin, and a ghrelin mimetic. , 2002, Diabetes.

[92]  T. Hökfelt,et al.  Hypocretin/Orexin‐ and melanin‐concentrating hormone‐expressing cells form distinct populations in the rodent lateral hypothalamus: Relationship to the neuropeptide Y and agouti gene‐related protein systems , 1998, The Journal of comparative neurology.

[93]  BMC Neuroscience BioMed Central , 2003 .

[94]  T. Hökfelt,et al.  The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[95]  R. Palmiter,et al.  Reward without Dopamine , 2003, The Journal of Neuroscience.

[96]  W. A. Owens,et al.  Deficits in dopamine clearance and locomotion in hypoinsulinemic rats unmask novel modulation of dopamine transporters by amphetamine , 2005, Journal of neurochemistry.

[97]  R. Palmiter,et al.  Deciphering a neuronal circuit that mediates appetite , 2012, Nature.

[98]  S. Dickson,et al.  Ghrelin directly targets the ventral tegmental area to increase food motivation , 2011, Neuroscience.

[99]  A. Murphy,et al.  Ghrelin O-acyltransferase (GOAT) is essential for growth hormone-mediated survival of calorie-restricted mice , 2010, Proceedings of the National Academy of Sciences.

[100]  J. Salamone,et al.  Dopamine, Behavioral Economics, and Effort , 2009, Front. Behav. Neurosci..

[101]  P. Duchamp-Viret,et al.  Fasting increases and satiation decreases olfactory detection for a neutral odor in rats , 2007, Behavioural Brain Research.

[102]  S. Sternson,et al.  Hunger States Switch a Flip-Flop Memory Circuit via a Synaptic AMPK-Dependent Positive Feedback Loop , 2011, Cell.

[103]  Xiao-Bing Gao,et al.  Ghrelin modulates the activity and synaptic input organization of midbrain dopamine neurons while promoting appetite. , 2006, The Journal of clinical investigation.