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AgRP neuron epigenomes across hunger states reveal that IRF3 mediates leptin's effects

ABSTRACT: AgRP neurons in the arcuate nucleus of the hypothalamus (ARC) coordinate homeostatic changes in appetite associated with fluctuations in food availability and leptin signaling. Identifying the relevant transcriptional regulatory pathways in these neurons has been a priority, yet such attempts have been stymied due to their low abundance and the rich cellular diversity of the ARC. Here we generated male mouse AgRP neuron-specific transcriptomic and chromatin accessibility profiles during three distinct hunger states of satiety, fasting-induced hunger, and leptin-induced hunger suppression. Cis-regulatory analysis of these integrated datasets enabled the identification of 28 putative hunger-promoting and 29 putative hunger-suppressing transcriptional regulators in AgRP neurons, 16 of which were predicted to be transcriptional effectors of leptin. Within our dataset, Interferon regulatory factor 3 (IRF3) emerged as a leading candidate mediator of leptin-induced hunger-suppression. Gain- and loss-of-function experiments in vivo confirm the role of IRF3 in mediating the acute satiety-evoking effects of leptin in AgRP neurons, while live-cell imaging in vitro indicate that leptin can activate neuronal IRF3 in a cell autonomous manner. Finally, we employ CUT&RUN to uncover direct transcriptional targets of IRF3 in AgRP neurons in vivo. Thus, our findings identify AgRP neuron-expressed IRF3 as a key transcriptional effector of the hunger-suppressing effects of leptin.

ORGANISM(S): Mus musculus

PROVIDER: GSE240484 | GEO | 2024/04/12

REPOSITORIES: GEO

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Project description:Neurons in the arcuate nucleus (ARC) sense the fed/fasted state and regulate hunger. ARCAgRP neurons release GABA, NPY and the melanocortin-4 receptor (MC4R) antagonist, AgRP, and are activated by fasting1-4. When stimulated, they rapidly and potently drive hunger5,6. ARCPOMC neurons, in contrast, release the MC4R agonist, α-MSH, and are viewed as the counterpoint to ARCAgRP neurons. They are regulated in an opposite fashion and their activity leads to decreased hunger2,4,7. Together, ARCAgRP and ARCPOMC neurons constitute the ARC feeding center. Against this, however, is the finding that ARCPOMC neurons, unlike ARCAgRP neurons, fail to affect food intake over the timescale of minutes to hours following opto- or chemogenetic stimulation5,8. This suggests a rapidly acting component of the ARC satiety pathway is missing. Here, we show that excitatory ARC neurons identified by expression of vesicular glutamate transporter 2 (VGLUT2) and the oxytocin receptor, unlike ARCPOMC neurons, rapidly cause satiety when chemo- or optogenetically manipulated. These glutamatergic ARC projections synaptically converge with GABAergic ARCAgRP projections on MC4R-expressing neurons in the paraventricular hypothalamus (PVHMC4R neurons), which are known to mediate satiety9. ARCPOMC neurons also send dense projections to the PVH. Importantly, the α-MSH they release post-synaptically potentiates glutamatergic synaptic activity onto PVHMC4R neurons – including that emanating from ARCVglut2 neurons. This suggests a means by which α-MSH can bring about satiety – via postsynaptic potentiation of this novel ARCVglut2 to PVHMC4R satiety circuit. Thus, while fast (GABA and NPY) and slow (AgRP) ARC hunger signals are delivered together by ARCAgRP neurons10,11, the temporally analogous satiety signals from the ARC, glutamate and α-MSH, are delivered separately by two parallel, interacting projections (from ARCVGLUT2 and ARCPOMC neurons). Discovery of this rapidly acting excitatory ARC → PVH satiety circuit, and its regulation by α-MSH, provides new insight into regulation of hunger/satiety.

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AgRP neuron epigenomes across hunger states reveal that IRF3 mediates leptin's effects

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