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Local Drd1-neurons input to subgroups of arcuate AgRP/NPY-neurons.

ABSTRACT: Obesity is a pandemic afflicting more than 300 million people worldwide, driven by consumption of calorically dense and highly rewarding foods. Dopamine (DA) signaling has been implicated in neural responses to highly palatable nutrients, but the exact mechanisms through which DA modulates homeostatic feeding circuits remains unknown. A subpopulation of arcuate (ARC) agouti-related peptide (AgRP)/neuropeptide Y (NPY) (ARC^AgRP/NPY+) neurons express the D(1A) dopamine receptor (Drd1) and are stimulated by DA, suggesting one potential avenue for dopaminergic regulation of food intake. Using patch clamp electrophysiology, we evaluated the responses of ARC Drd1-expressing (ARC^Drd1+) neurons to overnight fasting and leptin. Collectively, ARC^Drd1+ neurons were less responsive to caloric deficit than ARC^AgRP/NPY+ neurons; however, ARC^Drd1+ neurons were inhibited by the satiety hormone leptin. Using Channelrhodopsin-2-Assisted Circuit Mapping, we identified novel subgroups of ARC^Drd1+ neurons that inhibit or excite ARC^AgRP/NPY+ neurons. These findings suggest dopamine receptive neurons have multimodal actions in food intake circuits.

SUBMITTER: Chadwick SR

PROVIDER: S-EPMC9250019 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Cellular and synaptic reorganization of arcuate NPY/AgRP and POMC neurons after exercise.

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Antagonistic modulation of NPY/AgRP and POMC neurons in the arcuate nucleus by noradrenaline

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Optogenetic Stimulation of Arcuate Nucleus Kiss1 Neurons Reveals a Steroid-Dependent Glutamatergic Input to POMC and AgRP Neurons in Male Mice.

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Project description:The gut-derived hormone ghrelin exerts its effect on the brain by regulating neuronal activity. Ghrelin-induced feeding behaviour is controlled by arcuate nucleus neurons that co-express neuropeptide Y and agouti-related protein (NPY/AgRP neurons). However, the intracellular mechanisms triggered by ghrelin to alter NPY/AgRP neuronal activity are poorly understood. Here we show that ghrelin initiates robust changes in hypothalamic mitochondrial respiration in mice that are dependent on uncoupling protein 2 (UCP2). Activation of this mitochondrial mechanism is critical for ghrelin-induced mitochondrial proliferation and electric activation of NPY/AgRP neurons, for ghrelin-triggered synaptic plasticity of pro-opiomelanocortin-expressing neurons, and for ghrelin-induced food intake. The UCP2-dependent action of ghrelin on NPY/AgRP neurons is driven by a hypothalamic fatty acid oxidation pathway involving AMPK, CPT1 and free radicals that are scavenged by UCP2. These results reveal a signalling modality connecting mitochondria-mediated effects of G-protein-coupled receptors on neuronal function and associated behaviour.

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A Small Potassium Current in AgRP/NPY Neurons Regulates Feeding Behavior and Energy Metabolism.

Project description:Neurons that co-express agouti-related peptide (AgRP) and neuropeptide Y (NPY) are indispensable for normal feeding behavior. Firing activities of AgRP/NPY neurons are dynamically regulated by energy status and coordinate appropriate feeding behavior to meet nutritional demands. However, intrinsic mechanisms that regulate AgRP/NPY neural activities during the fed-to-fasted transition are not fully understood. We found that AgRP/NPY neurons in satiated mice express high levels of the small-conductance calcium-activated potassium channel 3 (SK3) and are inhibited by SK3-mediated potassium currents; on the other hand, food deprivation suppresses SK3 expression in AgRP/NPY neurons, and the decreased SK3-mediated currents contribute to fasting-induced activation of these neurons. Genetic mutation of SK3 specifically in AgRP/NPY neurons leads to increased sensitivity to diet-induced obesity, associated with chronic hyperphagia and decreased energy expenditure. Our results identify SK3 as a key intrinsic mediator that coordinates nutritional status with AgRP/NPY neural activities and animals' feeding behavior and energy metabolism.

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