Fasting, feasting and the glutamatergic synapse

Obesity has reached pandemic proportions, with the United States being one of the nations most affected. Among many lines of investigation aiming to counter obesity is the examination of how energy homeostasis and feeding behavior are regulated by the brain. Feeding behavior and weight regulation are largely controlled by the hypothalamic circuitry. Key components of this circuitry are two types of neurons in the arcuate nucleus (ARC) of the hypothalamus: the pro-feeding (anabolic) agouti-related protein (AgRP)-and neuropeptide Y (NPY)-expressing neurons (' AgRP neurons'), and the feeding-inhibitory (catabolic) proopio-melanocortin (POMC)-expressing neurons ('POMC neurons'). Circulating hormones are known to regulate the function of these neurons, including the neuromodulator ghrelin, which promotes AgRP neuron activation. Fasting has been shown to elicit activation of the anabolic AgRP neurons in part through ghrelin, resulting in an increase in feeding and subsequent weight gain. Conversely, the hormone leptin, which is secreted from adipocytes, activates the POMC neurons (Millington, 2007; Belgardt et al., 2009) to induce the release of melanocyte-stimulating hormone, which inhibits feeding. POMC neurons also release -endorphin, which inhibits AgRP activation through a negative-feedback loop. Despite detailed characterization of the feeding circuitry and its regulation by various peripheral hormones and metabolites, comparatively little attention has been paid to the synaptic regulation and plasticity of the neurons within the circuit, in which the firing rate of the circuit can by modulated by prior experience, including fasting. A recent pharmacological study by Yang et al. put forth a presynaptic mechanism to explain changes in the firing rate of this circuit (Yang et al., 2011), whereby an as-yet-unidentified hypothalamic neuron releases glutamate to activate AgRP neurons. According to this study, binding of the hormone ghrelin to the ghrelin receptor on this presynaptic neuron activates Ca 2+ /calmodulin-dependent protein kinase kinase (CAMKK), leading to the direct activation of AMP-activated kinase (AMPK). Activation of AMPK causes the release of ryanodine-sensitive Ca 2+ stores at the nerve terminal. The resulting increase in presynaptic Ca 2+ at these synapses thereby increases the probability of synaptic vesicle release from these terminals, culminating in the increased firing rate of AgRP neurons and an accompanying increase in feeding behavior. This synaptic plasticity is reversible, because POMC neurons can release -endorphin in response to leptin, activating opioid receptors on the presynaptic neuron. This, in turn, negatively regulates AMPK activity, reducing intracellular Ca 2+ levels, depressing the firing rate and, in effect, diminishing feeding. A more recent …