Role of Lateral Preoptic Neurotensin Receptor 1 Neurons in Weight Loss

Obesity remains a major global health challenge, with disruptions in the neural circuits that regulate energy balance. A neuropeptide neurotensin (Nts) acts via neurotensin receptor 1 (NtsR1) to regulate energy balance in different brain regions. The lateral preoptic area (LPO) expresses abundant NtsR1-expressing neurons while their role has not previously studied. The molecular profile and projection patterns via anterograde tracing supported that these neurons are likely to be involved in the energy regulation. Therefore, we hypothesized that NtsR1-expressing neurons in the LPO (LPO NtsR1 neurons) modulate ingestive behaviors and physiology that can lead to weight loss. To test the hypothesis, we injected NtsR1-Cre mice in the LPO with AAV-DIO-hM3D-mCherry to express excitatory Designer Receptors Exclusively Activated by Designer Drugs (DREADDq) in LPO NtsR1 neurons, permitting their activation after treatment with the DREADD ligand (0.3 mg/kg, i.p.). Acute DREADDq-mediated activation of LPO NtsR1 neurons modestly reduced homeostatic drinking and feeding behavior in normal-weight chow-fed mice compared to vehicle treatment, and the effects were more robust in diet-induced obese (DIO) mice. Sustained activation of LPO NtsR1 neurons for 3 consecutive days had no effect on body weight of chow-fed mice but significantly reduced feeding and body weight in DIO mice. However, DREADDq-mediated activation of LPO NtsR1 neurons did not alter locomotor activity, indicating that reduced feeding is not an artifact due to malaise or hyperactivity. Intriguingly, analysis in metabolic cages showed that activating LPO NtsR1 neurons also lowered respiratory exchange ratio (RER), indicative of biasing energy substrate usage from carbohydrate to fat. While the weight loss seems to be mainly driven by the reduced calorie intake, we investigated if the reward circuit is involved. The activation of LPO NtsR1 neurons reduced the motivation for the reward in fasted mice. Together, our findings identify a role for LPO NtsR1 neurons in modulating feeding, metabolism, rewards, and body weight, and suggest that these neurons and the NtsR1 system may be promising targets to support weight loss in obesity. This abstract was presented at the American Physiology Summit 2026 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.