Hypothalamic control of energy balance: insights into the role of synaptic plasticity  Marcelo O. Dietrich, Tamas L. Horvath  Trends in Neurosciences  Volume 36, Issue 2, Pages 65-73 (February 2013) DOI: 10.1016/j.tins.2012.12.005 Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 1 Organization of the melanocortin system in the arcuate nucleus. (a) The primary neurons of the melanocortin system are the orexigenic NPY/AgRP/GABA neurons and the anorexigenic POMC neurons (insert). Both populations of cell receive inhibitory and excitatory inputs that control neuronal function. (b) Example of synaptic coverage of the NPY/AgRP neurons in an image obtained using electron microscopy. (c) The NPY/AgRP neurons send inhibitory projections to the neighboring POMC cells, thus regulating the excitability of these cells [11,14,16]. Abbreviations: α-MSH, α-melanocyte stimulating hormone; AgRP, arcuate nucleus agouti-related protein; NPY neuropeptide Y; POMC, proopiomelanocortin. Trends in Neurosciences 2013 36, 65-73DOI: (10.1016/j.tins.2012.12.005) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 2 Molecular and biochemical players involved in NPY/AgRP neuronal activity and synaptic plasticity. (a) The NPY/AgRP neurons in the ARC are the main orchestrators of feeding behavior. Their activation leads to robust food intake [8,9], whereas their acute ablation in adults leads to feeding cessation [70,71]. Negative energy balance (e.g., fasting) leads to an increase in the levels of circulating ghrelin, which acts through GHSR receptors in the NPY/AgRP neurons to promote food intake [30,47,62,97]. Ghrelin signaling leads to the phosphorylation of AMPK, which then phosphorylates ACC, leading to a decrease in its enzymatic activity. This latter event decreases levels of malonyl-CoA, releasing CPT1 to uptake fatty acids inside the mitochondria. These fatty acids enter beta-oxidation to fuel the mitochondria, leading to the generation of ROS and ATP. ATP fuels neurons so that they are able to maintain activity even during periods of severe negative energy balance. ROS increase the activity of UCP2, which negatively feeds back to buffer the levels of ROS inside the cell. This loop allows proper and continuous activation of the NPY/AgRP neurons during periods of food scarcity [30]. (b) During fasting, NPY/AgRP neurons increase their activity and a constellation of changes occurs in the synaptic coverage of neurons in the ARC (Figure 3). Several molecules have already been identified as major players in the changes in activity and synaptic plasticity that occur in the NPY/AgRP neurons during negative energy balance [11,30,62,67]. Abbreviations: ACC, acetyl-CoA carboxylase; AgRP, ARC agouti-related protein; AMPK, AMP kinase; ARC, arcuate nucleus; CART, cocaine- and amphetamine-regulated transcript; CoA, co-enzyme A; GHSR, growth hormone secretagog receptor; CPT1, carnitine-dependent acyltransferase 1; MC4R, melanocortin receptor 4; NPY neuropeptide Y; POMC, proopiomelanocortin; ROS, reactive oxygen species; Sirt1, sirtuin 1; UCP2, uncoupling protein 2. Trends in Neurosciences 2013 36, 65-73DOI: (10.1016/j.tins.2012.12.005) Copyright © 2013 Elsevier Ltd Terms and Conditions

Figure 3 Synaptic plasticity in the melanocortin system in the ARC. Summary of synaptic changes and spine formation that occur in NPY/AgRP and POMC neurons in response to different metabolic and hormonal stimuli. (a) An orexigenic NPY/AgRP neuron that increases its activity in response to hormones released during negative energy balance (e.g., ghrelin). (b) An anorexigenic POMC neuron that is activated during states of satiety or by hormones, such as leptin and insulin. Negative energy balance (e.g., fasting) or ghrelin promotes an increase in the number of excitatory inputs to NPY/AgRP neuron perikarya, while decreasing the number of excitatory inputs to POMC neuron perikarya [56,58,62]. Additionally, fasting also leads to an increase in the number of dendritic spines in the NPY/AgRP neurons, in a mechanism dependent on NMDA receptors [67]. Positive energy balance in the form of a high-fat diet leads to decreases in the number of excitatory inputs to NPY/AgRP neurons and inhibitory inputs to POMC neurons. In addition, a high-fat diet increases excitatory inputs to the POMC neuron perikarya. The constellation of changes that occurs during high-fat feeding switches the physiological set point of the melanocortin system in the ARC towards activation of POMC neurons, while decreasing excitability of NPY/AgRP neurons [76]. Finally, leptin promotes changes in the synaptic coverage of NPY/AgRP and POMC neurons similar to those in response to high-fat feeding. Specifically, it increases the excitability of POMC neurons by increasing the number of excitatory synaptic inputs to these neurons. In addition, it also increases the number of inhibitory inputs and decreases the number of excitatory inputs onto NPY/AgRP neurons [56,62]. Abbreviations: AgRP, ARC agouti-related protein; ARC, arcuate nucleus; NPY neuropeptide Y; POMC, proopiomelanocortin. Trends in Neurosciences 2013 36, 65-73DOI: (10.1016/j.tins.2012.12.005) Copyright © 2013 Elsevier Ltd Terms and Conditions