Document text
Principal Investigator: Jariel Yamil Ramirez-Virella
Organization: MICHIGAN STATE UNIVERSITY
Fiscal Year: 2024
Award: $40,506
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
Overconsumption of food and reduced physical activity cause obesity, but limited
understanding of the neuronal systems regulating these behaviors has hindered development of
therapies to support weight loss. Intriguingly, injecting the neuropeptide neurotensin (Nts) into the
ventral tegmental area (VTA) of the brain suppresses feeding and promotes physical activity, the
ideal combination of behaviors for reducing weight. These effects are likely mediated via the
subset of dopamine neurons within the VTA that express Neurotensin Receptor-1 (NtsR1) and
indeed, activating these neurons in obese mice restrains feeding, increases physical activity, and
causes weight loss. Taken together, these data suggest that augmenting Nts-NtsR1 signaling via
the VTA may be useful to safely promote weight loss. Here I will test the hypothesis that
endogenous or pharmacological enhancement of Nts-NtsR1 signaling will promote weight loss
behaviors. In Aim 1 I will augment endogenous Nts input to the VTA. Specifically, I will combine
NtsCre mice and optogenetics to activate lateral hypothalamic area neurotensin (LHANts) neurons
projecting to the VTA, which have been implicated in promoting weight loss. However, activating
all LHANts neurons simultaneously invokes voracious drinking (putatively via projections
elsewhere) that mitigates weight loss. My work will reveal if isolating the endogenous LHANts
VTA NtsR1 circuit can optimally promote weight loss, without invoking undesirable effects. In Aim
2 I will determine if pharmacological NtsR1 agonists promote weight loss behaviors. NtsR1 is a
G-Protein Coupled Receptor that, upon ligand binding to the receptor, can transduce intracellular
signaling via Gq-coupled and/or a ß-arrestin pathways, but it remains unclear if one or both of
these pathways potentiate weight loss effects. To assess which NtsR1 receptor signaling pathway
invokes weight loss, I will administer a general NtsR1 agonist that promotes both Gq-coupled and
ß-arrestin signaling or a compound that exclusively activates the ß-arrestin pathway. Agonists will
be delivered intra-VTA or systemically to elucidate the brain site and intracellular pathways by
which NtsR1 agonism mediates weight loss. Taken together, these data will reveal endogenous
and pharmacological mechanisms by which Nts-NtsR1 modulates body weight and may be useful
to guide future development of strategies to treat obesity.
Terms: <Agonist><Behavior><Body Weight><Body Weight decreased><Brain><Brain Nervous System><Cell Communication and Signaling><Cell Signaling><Coupled><DA Neuron><Data><Development><Disease><Disorder><Dopamine neuron><Drugs><Eating><Encephalon><Energy Expenditure><Energy Metabolism><Feeding behaviors><Fellowship><Food><Food Intake><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><G-Proteins><GPCR><GTP-Binding Proteins><GTP-Regulatory Proteins><Goals><Guanine Nucleotide Coupling Protein><Guanine Nucleotide Regulatory Proteins><Hypothermia><Ingestion><Ingestive Behavior><Intracellular Communication and Signaling><Lateral Hypothalamic Area><Learning><Ligand Binding><Locomotor Activity><Measures><Mediating><Medication><Mice><Mice Mammals><Motor Activity><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System Diseases><Nervous System Disorder><Neural Cell><Neurocyte><Neurologic Disorders><Neurological Disorders><Neurons><Neuropeptides><Neurotensin><Neurotensin Receptors><Obese Mice><Obesity><Outcome><Pathway interactions><Pharmaceutical Preparations><Pharmacology><Physical activity><Population><Psychological reinforcement><Receptor Protein><Receptor Signaling><Reinforcement><Research><Resolution><Rewards><Rodent><Rodentia><Rodents Mammals><Role><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Site><Source><Stress><System><Techniques><Testing><Ventral Tegmental Area><Water Intake><Water consumption><Weight><Weight Gain><Weight Increase><Weight Loss><Weight Reduction><Work><adiposity><antagonism><antagonist><arm><arrestin B><beta-arrestin><biological signal transduction><body weight gain><body weight increase><body weight loss><career><combat><corpulence><develop therapy><developmental><dopaminergic neuron><drinking><drug/agent><eat less><effective therapy><effective treatment><energy balance><feeding><feeding-related behaviors><food consumption><ingest><insight><intervention development><mouse model><murine model><natural hypothermia><neural><neural mechanism><neurological disease><neuromechanism><neuronal><nutrient intake activity><ob/ob mouse><obesity intervention><obesity therapy><obesity treatment><optogenetics><pathway><pharmacologic><receptor><reduced eating><reduced food intake><resolutions><restraint><social role><therapy development><treatment development><ventral tegmentum><weights><wt gain><wt-loss><β-arrestin>