Activation of VTA NtsR1 Neurons Promotes Weight Loss Behaviors

Abstract

Dopamine (DA) neurons in the ventral tegmental area (VTA) modulate motivation to engage in physical activity and food intake, dual behaviors that are disrupted in obesity. However, the functional heterogeneity of VTA DA neurons, and lack of molecular markers to distinguish them, has prevented determination of which DA neurons might be leveraged to support weight loss behaviors. We identified a distinct subset of VTA DA neurons defined by their expression of neurotensin receptor‐1 (NtsR1) and we hypothesized that these “VTA NtsR1 neurons” modulate feeding restraint and physical activity that could support weight loss. To test this hypothesis, we expressed Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in the VTA NtsR1 neurons of normal weight and diet‐induced obese mice, permitting in vivo activation of VTA NtsR1 neurons by treatment with the DREADD‐ligand clozapine‐N‐oxide (CNO). Acute activation of VTA NtsR1 neurons (24hr) in normal weight and diet‐induced obese mice significantly decreased body weight by reducing food intake and increasing physical activity. Moreover, the weight loss of diet‐induced obese mice was maintained with daily activation of VTA NtsR1 over 7d. Intriguingly, activation of VTA NtsR1 neurons also suppressed how much mice would work to obtain sucrose rewards even when there was high motivation to consume (e.g. in fasted mice or diet‐induced obese mice.) These data suggest that VTA NtsR1 neurons may be useful to support weight loss behavior. Yet, the translational potential of NtsR1 was previously dismissed due to the broad expression of NtsR1 throughout the brain and periphery, and data that systemic NtsR1 agonists cause adverse hypothermia and vasodepressor responses. However, we found that specifically activating VTA NtsR1 neurons does not alter blood pressure, core body temperature or anxiety behavior. Thus, activation of VTA NtsR1 neurons during states of high‐appetitive drive such as fasting and obesity promotes dual behaviors that support weight loss without causing adverse cardiorespiratory effects or stress responses. In the future, strategies to selectively modulating VTA NtsR1 neurons could provide a safe, effective avenue for weight loss.Support or Funding InformationSupported by funding from the National Institutes of Health to Perez‐Bonilla (T32GM092715) and Leinninger (R01‐DK103808)