Dopamine-inhibited POMCDrd2+ neurons in the ARC acutely regulate feeding and body temperature
Isabella Gaziano, … , Peter Kloppenburg, Jens C. Brüning
Isabella Gaziano, … , Peter Kloppenburg, Jens C. Brüning
Published November 8, 2022
Citation Information: JCI Insight. 2022;7(21):e162753. https://doi.org/10.1172/jci.insight.162753.
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Research Article Endocrinology Neuroscience

Dopamine-inhibited POMCDrd2+ neurons in the ARC acutely regulate feeding and body temperature

Abstract

Dopamine acts on neurons in the arcuate nucleus (ARC) of the hypothalamus, which controls homeostatic feeding responses. Here we demonstrate a differential enrichment of dopamine receptor 1 (Drd1) expression in food intake–promoting agouti related peptide (AgRP)/neuropeptide Y (NPY) neurons and a large proportion of Drd2-expressing anorexigenic proopiomelanocortin (POMC) neurons. Owing to the nature of these receptors, this translates into a predominant activation of AgRP/NPY neurons upon dopamine stimulation and a larger proportion of dopamine-inhibited POMC neurons. Employing intersectional targeting of Drd2-expressing POMC neurons, we reveal that dopamine-mediated POMC neuron inhibition is Drd2 dependent and that POMCDrd2+ neurons exhibit differential expression of neuropeptide signaling mediators compared with the global POMC neuron population, which manifests in enhanced somatostatin responsiveness of POMCDrd2+ neurons. Selective chemogenetic activation of POMCDrd2+ neurons uncovered their ability to acutely suppress feeding and to preserve body temperature in fasted mice. Collectively, the present study provides the molecular and functional characterization of POMCDrd2+ neurons and aids our understanding of dopamine-dependent control of homeostatic energy-regulatory neurocircuits.

Authors

Isabella Gaziano, Svenja Corneliussen, Nasim Biglari, René Neuhaus, Linyan Shen, Tamara Sotelo-Hitschfeld, Paul Klemm, Lukas Steuernagel, Alain J. De Solis, Weiyi Chen, F. Thomas Wunderlich, Peter Kloppenburg, Jens C. Brüning

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Figure 1

Drd1 and Drd2 colocalize on distinct neuronal populations within the ARC.

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Drd1 and Drd2 colocalize on distinct neuronal populations within the ARC...
(A) mRNA expression levels of dopamine receptor isoforms as assessed by quantitative PCR of C57BL/6N ARC micropunches. Data are represented as mean ± SEM, n = 8. (B) Drd1 and Drd2 mRNA expression levels in bulk RNA sequencing of AgRP/NPY or POMC neurons from random fed mice published by Henry et al. (21). Data are represented as heatmap of counts in transcripts per million per replicate. (C) Representative images of RNA in situ hybridization against Pomc and Agrp (top) and Drd1 and Drd2 (bottom) in ARC of C57BL/6N mice. AgRP/NPY and POMC neurons are indicated by white or red outlines, respectively. Scale bars: 200 μm in overviews (left), 20 μm in respective magnifications (right). (D and E) Percentage of Drd1 and/or Drd2 coexpressing AgRP (D) or POMC (E) neurons as quantified from RNA in situ hybridization in C57BL/6N mice (C). Data are represented as mean ± SEM; n = 3–4. (F) Representative images of RNA in situ hybridization against Pomc (top) and Drd2, Glp1r, and Lepr (bottom) in ARC of C57BL/6N mice. POMCDrd2– neurons are outlined in white, POMCDrd2+ neurons in magenta. Scale bars represent 50 μm in the overviews (left) and 20 μm in the respective magnifications (right). (G) Percentages of POMCDrd2+ neurons coexpressing Lepr or Glp1r as quantified from RNA in situ hybridization in C57BL/6N mice (F). Data are represented as mean ± SEM; n = 4. (A and G) No statistical tests applied. (B) P values calculated using paired, 2-tailed Wilcoxon rank tests. (D and E) P values calculated using 1-way ANOVA with Tukey’s post hoc multiple comparisons test with a single pooled variance. **P < 0.01. ***P < 0.001. ****P < 0.0001.