Editors' ChoiceMetabolism

Hunger Circuit

Sci. Signal.  27 Sep 2011:
Vol. 4, Issue 192, pp. ec269
DOI: 10.1126/scisignal.4192ec269

Activation of neurons that release the neuropeptide Agouti-related protein (AgRP) neurons elicits feeding, whereas activation of neurons that release proopiomelanocortin (POMC) neurons inhibits feeding (see Dietrich and Horvath). AgRP neurons inhibit the activity of POMC neurons. Yang et al. performed whole-cell patch recordings on AgRP neurons in brain slices from food-deprived mice or mice fed ad libitum and found that food deprivation increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), which correlate with the amount of neurotransmitter released from presynaptic terminals. This effect required release of Ca2+ from intracellular stores mediated by ryanodine receptors. The hormone ghrelin is released from the gut in response to food deprivation, and ghrelin treatment of brain slices from fed mice or ghrelin injection into fed mice increased the frequency of mEPSCs. Conversely, a ghrelin receptor antagonist prevented the increase in mEPSC frequency in brain slices from food-deprived mice, whether it was added to the slices or injected into animals. Ghrelin activation of AgRP neurons triggered a positive feedback loop in which CAMKK (Ca2+/calmodulin-dependent protein kinase) activated AMPK (adenosine 5'-monophosphate–activated protein kinase), which in turn stimulated Ca2+ release from ryanodine-sensitive stores. This positive feedback loop maintained persistent increased activity of AgRP neurons in a ghrelin-independent manner for several hours once induced and was eventually attenuated by the anorexic hormone leptin, which triggered release of an opioid from POMC neurons. Thus, in response to food deprivation, ghrelin activates a positive feedback loop that maintains increased activity of AgRP neurons to drive feeding behavior until satiety is reached, triggering down-regulation of the activity of AgRP neurons through leptin-mediated stimulation of POMC neurons.

Y. Yang, D. Atasoy, H. H. Su, S. M. Sternson, Hunger states switch a flip-flop memory circuit via a synaptic AMPK-dependent positive feedback loop. Cell 146, 992–1003 (2011). [PubMed]

M. O. Dietrich, T. L. Horvath, Synaptic plasticity of feeding circuits: Hormones and hysteresis. Cell 146, 863–865 (2011). [PubMed]