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bioRxiv · 10.1101/2022.06.27.497778

Mice lacking dopamine production in neurotensin receptor 1 neurons voluntarily undergo time-restricted feeding of high fat diet and resist obesity

Farahmand, F.·Sidikpramana, M.·Yousef, B.·Sharif, S.·Shao, K.·Tang, Q.·Leinninger, G.·Guler, A.·Steele, A.
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Abstract

The introduction of processed foods high in fat and sugars has caused a dramatic increase in obesity in humans. Diet-induced obesity (DIO) can be modeled in laboratory mice by increasing the fat content of their diet. Previously, it was determined that mice lacking dopamine receptor 1 (Drd1) are completely resistant to DIO and do not eat as much food during the day as control mice. Surprisingly, when Drd1 is restored to the suprachiasmatic nucleus (SCN), which is the central regulator of circadian rhythms, these mice increase day-eating and become obese. The source of dopamine in the SCN is the ventral tegmental area (VTA), but the genetic identity of the dopamine neurons is unknown. Here we create conditional deletion mutants for tyrosine hydroxylase (TH) using neurotensin receptor 1 (Ntsr1) Cre and other Cre drivers and measure feeding and body weight homeostasis on standard and high fat diets. Control mice were susceptible to DIO and overate during the day whereas Ntsr1-Cre conditional knockouts for TH mice did not increase day-eating, nor did they gain much weight on HFD. We used an adeno-associated virus to selectively restore TH to the VTA Ntsr1 neurons and observed an increase in body weight and increased day-eating of HFD. These results implicate VTA Ntsr1 dopamine neurons as promoting out-of-phase feeding behavior on a high fat diet that could be an important contributor to diet-induced obesity.

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Farahmand, F., Sidikpramana, M., Yousef, B., Sharif, S., Shao, K., Tang, Q., Leinninger, G., Guler, A., Steele, A.. 2022-06-30. Mice lacking dopamine production in neurotensin receptor 1 neurons voluntarily undergo time-restricted feeding of high fat diet and resist obesity. https://doi.org/10.1101/2022.06.27.497778

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