The small peptide Neurotensin (Nts) is implicated in myriad processes including analgesia, thermoregulation, reward, arousal, blood pressure and modulation of feeding and body weight. Alterations in Nts have recently been described in individuals with obesity or eating disorders, suggesting that disrupted Nts signaling may contribute to body weight disturbance. Curiously, Nts mediates seemingly opposing regulation of body weight via different tissues. Peripherally-acting Nts promotes fat absorption and weight gain, while central Nts signaling suppresses feeding and weight gain. Thus, because Nts is pleiotropic, a location-based approach must be used to understand its contributions to disordered body weight and whether the Nts system might be leveraged to improve metabolic health. Here we review the role of Nts signaling in the brain to understand the sites, receptors and mechanisms by which Nts can promote behaviors that modify body weight. New techniques permitting site-specific modulation of Nts and Nts receptor- expressing cells suggest that, even in the brain, not all Nts circuitry exerts the same function. Intriguingly, there may be dedicated brain regions and circuits via which Nts specifically suppresses feeding behavior and weight gain vs. other Nts-attributed physiology. Defining the central mechanisms by which Nts signaling modifies body weight may suggest strategies to correct disrupted energy balance, as needed to address overweight, obesity and eating disorders.

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Central neurotensin signaling via neurotensin receptor-1 (NtsR1) modulates various aspects of physiology, including suppressing feeding and promoting locomotor activity that can support weight loss. However, it remains unclear when and where NtsR1 expression contributes to control of body weight vs. other effects. We previously showed that activating ventral tegmental area (VTA) dopamine (DA) neurons that express NtsR1 promotes weight loss. We therefore hypothesized that deleting NtsR1 from DA neurons would promote weight gain by increasing food intake and decreasing physical activity. In contrast, developmental deletion of NtsR1 from DA neurons (by crossing DATCre mice with NtsR1flox/flox mice) had no impact on the feeding or body weight of mice fed a chow diet, though it augmented locomotor activity. Developmental deletion of NtsR1 from DA neurons protected mice from diet-induced obesity, but not via altering feeding, physical activity, or energy expenditure. Given that NtsR1 may exert distinct roles within development vs. adulthood, we then examined the impact of adult-onset deletion of NtsR1 from VTA DA neurons. We injected adult NtsR1flox/flox mice in the VTA with adeno associated virus to Cre-dependently delete NtsR1 in the VTA (VTAR1Null mice) and compared them to mice with intact NtsR1 (Controls). Again, in contrast to our hypothesis, VTAR1Null mice gained less weight than Controls while on normal chow or high fat diets. Moreover, VTAR1Null mice exhibited blunted feeding after fasting, suggesting a role for NtsR1 in adult VTA DA neurons in coordinating energy need and intake. Altogether, these data suggest that intact expression of NtsR1 in DA neurons is necessary for appropriate regulation of body weight, but a lack of NtsR1 in the developing vs. adult DA system protects from weight gain via different mechanisms. These findings emphasize the need for temporal and site-specific resolution to fully understand the role of NtsR1 within the brain.

The dopamine (DA) system is essential for motivated feeding and locomotion, but disruption of this system is implicated in the development of obesity and low body weight, namely anorexia nervosa. All DA neurons transiently express the neurotensin receptor‐1 (NtsR1) during development, suggesting that this receptor may contribute to the establishment and/or function of the DA system. Thus, we hypothesized that lacking NtsR1 expression in DA neurons impairs the function of the DA system and DA‐dependent feeding, locomotor activity, and anxiety behaviors. To test this, we crossed DATCre/+ and NtsR1flox/floxmice to generate mice with intact NtsR1 (Controls ‐ DAT+/+; NtsR1flox/flox) or mice in which NtsR1 was selectively deleted from DA neurons (DATCre/+; NtsR1flox/floxmice). We then assessed mice of each genotype and sex for feeding and physical activity, DA‐dependent behaviors and body weight. Feeding and body weight were similar in Control mice and those lacking NtsR1 from DA neurons. However, mice lacking NtsR1 in DA neurons exhibited more locomotor activity than Control mice. This altered locomotor activity was not due to altered stress or anxiety like behaviors, nor differences in dopamine‐ dependent behaviors, as these were similar between Control and NtsR1‐deficient mice. Thus, in contrast to our hypothesis, developmental deletion of NtsR1 deletion from dopamine neurons does not disrupt regulation of body weight or behavior, and is likely not a pathogenetic contributor to disordered body weight.