Acute and Long-Term Suppression of Feeding Behavior by POMC Neurons in the Brainstem and Hypothalamus, Respectively

Abstract

POMC-derived melanocortins inhibit food intake. In the adult rodent brain, POMC-expressing neurons are located in the arcuate nucleus (ARC) and the nucleus tractus solitarius (NTS), but it remains unclear how POMC neurons in these two brain nuclei regulate feeding behavior and metabolism differentially. Using pharmacogenetic methods to activate or deplete neuron groups in separate brain areas, in the present study, we show that POMC neurons in the ARC and NTS suppress feeding behavior at different time scales. Neurons were activated using the DREADD (designer receptors exclusively activated by designer drugs) method. The evolved human M3-muscarinic receptor was expressed in a selective population of POMC neurons by stereotaxic infusion of Cre-recombinase-dependent, adenoassociated virus vectors into the ARC or NTS of POMC-Cre mice. After injection of the human M3-muscarinic receptor ligand clozapine-N-oxide (1 mg/kg, i.p.), acute activation of NTS POMC neurons produced an immediate inhibition of feeding behavior. In contrast, chronic stimulation was required for ARC POMC neurons to suppress food intake. Using adeno-associated virus delivery of the diphtheria toxin receptor gene, we found that diphtheria toxin-induced ablation of POMC neurons in the ARC but not the NTS, increased food intake, reduced energy expenditure, and ultimately resulted in obesity and metabolic and endocrine disorders. Our results reveal different behavioral functions of POMC neurons in the ARC and NTS, suggesting that POMC neurons regulate feeding and energy homeostasis by integrating long-term adiposity signals from the hypothalamus and short-term satiety signals from the brainstem.

17α‐estradiol acts through hypothalamic pro‐opiomelanocortin expressing neurons to reduce feeding behavior

“…Deletion of nPE2, nPE1, or insertion of a transcription‐blocking neo selection cassette into the vicinity of the two hypothalamic neuronal Pomc enhancers reduces hypothalamic Pomc expression to ~80%, ~30%, or ~2% of wild‐type controls, respectively (Lam et al, 2015). A reduction in hypothalamic Pomc expression at or below ~30% of wild‐type controls in these mice results in a functional loss of Pomc ‐mediated regulation of body mass (Bumaschny et al., 2012; Lam et al., 2015; Zhan et al., 2013). Therefore, we hypothesized that if 17α‐E2 were to act selectively by increasing hypothalamic Pomc expression, the treatment effects on body mass and food intake would be disrupted in mutant mice lacking nPE1 ( Pomc Δ1 ) or those containing the Pomc transcription‐blocking neo selection cassette ( Pomc neo ).…”

Resolving Behavioral Output via Chemogenetic Designer Receptors Exclusively Activated by Designer Drugs

“…This subpopulation is critical for sustaining apposite levels of energy balance as shown via genetic knock-out, ablation, and pharmacology approaches (Fan et al, 1997;Hahn et al, 1998;Yaswen et al, 1999;Gropp et al, 2005;Xu et al, 2005;Greenman et al, 2013;Zhan et al, 2013). To explore the acute role of ARC POMC neurons in vivo, excitatory and inhibitory DREADDs were used to alter activity in an acute fashion and body weight and food intake were monitored over hours to days.…”

“…To explore the acute role of ARC POMC neurons in vivo, excitatory and inhibitory DREADDs were used to alter activity in an acute fashion and body weight and food intake were monitored over hours to days. Importantly, ex vivo electrophysiology established CNO-mediated changes in ARC POMC activity in a bidirectional manner, depending on the type of DREADD used (Atasoy et al, 2012; Zhan et al, 2013). Supporting the notion that the prolonged kinetics of a-melanocyte-stimulating hormone (aMSH), a major peptide cleaved from the pomc gene, affects energy balance, CNO-mediated activation of ARCPOMC neurons significantly lowered food intake over several hours (Steculorum et al, 2016) and externding this treatment lowered food intake and body weight over several days (Zhan et al, 2013), while chronic silencing this population markedly escalated food consumption over 24 hours (Atasoy et al, 2012).…”

“…While this may be a concern, viral and transgenic expression methods express DREADDs at high levels, likely circumventing the problem of desensitization after repeated activation (for review, see . Also, studies using prolonged CNO delivery have not reported difficulty with repeated activation of DREADDs Zhan et al, 2013). Finally, although DREADDs often fuse or are tagged with fluorophore tags (such as mCherry, GFP, and mCitrine), several laboratories have reported that detection of these fluorophores in their native state can prove difficult with DREADDs.…”

Selective Manipulation of Neural Circuits

“…Viruses carrying a driver-dependent genetic tool have been injected into the brain region of the cell type-specific driver mouse lines where the circuit originates [90][91][92][93][94][95][96]. In this approach, the driver transgene defines the cell types, and the injection of virus provides regional specificity.…”