A novel neuron population that selectively controls metabolism

The brain is crucial in regulating energy balance, the relationship between energy intake and energy expenditure. The disruption of this process can lead to obesity and other metabolic disease. Leptin acts on neurons in the arcuate nucleus of the hypothalamus to increase energy expenditure through brown adipose tissue (BAT) thermogenesis and decrease body weight. We discovered a novel population of neurons in the arcuate nucleus, arcuate phosphoinositide interacting regulator of the transient receptor potential (Pirt) neurons. These neurons are inhibitory, respond to leptin and regulate metabolism. Our unpublished results show that activating arcuate Pirt neurons decreases BAT thermogenesis and metabolism. To investigate whether the activation of arcuate Pirt neurons regulates feeding, we bilaterally injected an adeno-associated virus, which expresses the stimulatory intersectional designer receptor exclusively activated by designer drugs (DREADDs; hM3D(Gq)) only following recombination by both Cre and Flp recombinases (AAV-Cre ON /Flp ON -hM3Dq-HA), into the ARC of male and female Pirt-Cre::Slc32a1-Flp mice (n=11; 6 injections, 100 nL each) to activate arcuate Pirt neurons. After a 3-week recovery period to allow for transgene expression, we intraperitoneally injected the pharmacologically inert ligand, clozapine N-oxide (CNO: 1 mg/kg), or saline vehicle in ad libitum -fed mice during the 12-hour light and dark cycles and measured food intake after 30 minutes, 1 hour, 2 hours, and 4 hours on alternating days, We found that activating arcuate Pirt neurons does not affect food intake (light cycle: two-way ANOVA, F (1, 22) = 0.2197, P=0.6439; dark cycle: two-way ANOVA, F (1, 20) = 1.641, P=0.2149). Next, we investigated whether the stimulation of arcuate Pirt neurons modulates BAT temperature, using the same mice expressing hM3D(Gq) (n=3). We surgically implanted telemetry probes – (1) a temperature transponder under the pads of the interscapular near the Sulzer’s vein to measure BAT temperature and (2) a temperature logger in the peritoneal regions to measure core body temperature. We intraperitoneally injected the pharmacologically inert ligand, deschlorozapine (DCZ: 2.5 mg/kg), or saline vehicle in overnight-fasted mice during the 12-hour light cycle and used a transponder reader to measure BAT temperature, while the temperature logger automatically and simultaneously measured core body temperatures hourly over 8 hours on alternating days. Our preliminary data indicates that activating arcuate Pirt neurons with DCZ decreases BAT and core body temperatures and oxygen consumption, compared to saline treatment (n=3 mice). In sum, our study indicates that arcuate Pirt neurons decrease metabolism. Understanding the role of arcuate Pirt neurons in energy metabolism will advance our knowledge of how the brain regulates energy balance, fostering the development of targeted therapies to treat metabolic diseases such as obesity. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.