Identification of Novel Neurocircuitry Through Which Leptin Targets Multiple Inputs to the Dopamine System to Reduce Food Reward Seeking

Omrani, Azar; Vrind, Véronne A J de; Lodder, Bart; Stoltenborg, Iris; Kooij, K.; Wolterink-Donselaar, Inge G.; Luijendijk-Berg, Mieneke C M; Garner, Keith M.; Sant, Lisanne J. van ’t; Rozeboom, Annemieke; Dickson, Suzanne L.; Adan, Roger A.H.

doi:10.1016/j.biopsych.2021.02.017

Cited by 23 publications

(28 citation statements)

References 48 publications

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“…These findings imply the existence of an isolated food-specific population within the vast population of LH GABA neurons. Since leptin decreases food motivation by inhibiting LH LepR neurons 14, 15, 18 , and LH LepR neurons have been reported to be associated with feeding 16, 18 . Therefore, we hypothesised that LH LepR neurons may represent this food-specific subpopulation.…”

Section: Resultsmentioning

confidence: 99%

“…Heterogenous GABAergic neurons are widely distributed in the lateral hypothalamus (LH) and are involved in various motivated behaviours, including feeding 9, 10, 11, 12, 13 . Among LH GABA neurons, leptin receptor (LepR) neurons are reported to be associated with feeding behaviour, although the results of previous studies remain controversial 14, 15, 16, 17, 18 . To investigate whether distinct neural populations separately encode motivation for food-seeking and/or evaluating, we focused on LH GABA and LH LepR neurons using these newly developed behavioural paradigms.…”

Section: Introductionmentioning

confidence: 99%

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Neural Mechanism of Hunger-gated Food-seeking and Evaluating

Lee

Song

Kim

et al. 2020

Preprint

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Agouti-related protein (AgRP) has been believed to be the main driver of feeding behaviors ever since its discovery. However, recent studies using fiber photometry and optogenetics proved that feeding behaviors are not directly driven by AgRP neurons (temporal discrepancy between neuronal activity and behavior). To resolve this paradox, we conducted novel multi-phase feeding experiments to scrutinize the dynamics of AgRP. Fiber photometry study showed that AgRP neurons start to deactivate even before the initiation of the food search phase. Using optogenetics, we could prove that the feeding behavior induced by AgRP neuron activation had substantial temporal delay and the feeding behavior was sustained for substantial time even after cessation of optogenetic activation. These results indicate that AgRP neurons are not the direct driver of feeding behavior and another downstream neuron is the driver of feeding behavior. Leptin receptor (LepR) neurons in the lateral hypothalamus (LH). LH LepR neurons were activated before voluntary food search behavior initiation and showed robust increase after food approach behavior. Artificial activation of LH LepR neurons drives food search and food approach behavior. In accordance, chemogenetic activation of LepR neurons increased food search and food approach behaviors. Lastly, slice calcium imaging results showed the possibility that NPY from the AgRP neurons could be the downstream neuromodulator of AgRP neuron, driving LH LepR neuron activation. Overall, our study shows that AgRP neurons are not the direct drivers of feeding behavior, whereas LH LepR neurons directly drive sustained food seeking behavior.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Neural Mechanism of Hunger-gated Food-seeking and Evaluating

Lee

Song

Kim

et al. 2020

Preprint

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“…One interpretation of our results is, therefore, that decreased motivation is the result of chemogenetic activation of VTA GABA-LepR neurons that reduce VTA DA activity. Indeed, it was recently found using optogenetic-assisted circuit mapping that VTA GABA neurons expressing the leptin receptor are activated by leptin and directly inhibit VTA DA neurons ( 37 ). Similarly, inhibitory input from the lateral hypothalamus to the VTA was shown to inhibit GABA neurons and increase dopamine release in the nucleus accumbens ( 38 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

Leptin Receptor Expressing Neurons in the Substantia Nigra Regulate Locomotion, and in The Ventral Tegmental Area Motivation and Feeding

et al. 2021

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Leptin is an anorexigenic hormone, important in the regulation of body weight. Leptin plays a role in food reward, feeding, locomotion and anxiety. Leptin receptors (LepR) are expressed in many brain areas, including the midbrain. In most studies that target the midbrain, either all LepR neurons of the midbrain or those of the ventral tegmental area (VTA) were targeted, but the role of substantia nigra (SN) LepR neurons has not been investigated. These studies have reported contradicting results regarding motivational behavior for food reward, feeding and locomotion. Since not all midbrain LepR mediated behaviors can be explained by LepR neurons in the VTA alone, we hypothesized that SN LepR neurons may provide further insight. We first characterized SN LepR and VTA LepR expression, which revealed LepR expression mainly on DA neurons. To further understand the role of midbrain LepR neurons in body weight regulation, we chemogenetically activated VTA LepR or SN LepR neurons in LepR-cre mice and tested for motivational behavior, feeding and locomotion. Activation of VTA LepR neurons in food restricted mice decreased motivation for food reward (p=0.032) and food intake (p=0.020), but not locomotion. In contrast, activation of SN LepR neurons in food restricted mice decreased locomotion (p=0.025), but not motivation for food reward or food intake. Our results provide evidence that VTA LepR and SN LepR neurons serve different functions, i.e. activation of VTA LepR neurons modulated motivation for food reward and feeding, while SN LepR neurons modulated locomotor activity.

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“…have proven that leptin inhibits mesolimbic dopamine neuronal activity, decreasing the reward value of sucrose ( 98 ), and recently, Omran et al. have proposed that leptin reduces the pleasure of food activating via inhibitory GABA neurons in VTA that directly regulate dopamine neurons ( 99 ). It is important to note that satiety induced by the melanocortin system is antagonized by NPY/AgRP neurons.…”

Section: The Circadian System: An Orchestra Of Signals Synchronizes F...mentioning

confidence: 99%

Chrono-communication and cardiometabolic health: The intrinsic relationship and therapeutic nutritional promises

Senesi

Ferrulli²,

Luzi³

et al. 2022

Front. Endocrinol.

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Circadian rhythm, an innate 24-h biological clock, regulates several mammalian physiological activities anticipating daily environmental variations and optimizing available energetic resources. The circadian machinery is a complex neuronal and endocrinological network primarily organized into a central clock, suprachiasmatic nucleus (SCN), and peripheral clocks. Several small molecules generate daily circadian fluctuations ensuring inter-organ communication and coordination between external stimuli, i.e., light, food, and exercise, and body metabolism. As an orchestra, this complex network can be out of tone. Circadian disruption is often associated with obesity development and, above all, with diabetes and cardiovascular disease onset. Moreover, accumulating data highlight a bidirectional relationship between circadian misalignment and cardiometabolic disease severity. Food intake abnormalities, especially timing and composition of meal, are crucial cause of circadian disruption, but evidence from preclinical and clinical studies has shown that food could represent a unique therapeutic approach to promote circadian resynchronization. In this review, we briefly summarize the structure of circadian system and discuss the role playing by different molecules [from leptin to ghrelin, incretins, fibroblast growth factor 21 (FGF-21), growth differentiation factor 15 (GDF15)] to guarantee circadian homeostasis. Based on the recent data, we discuss the innovative nutritional interventions aimed at circadian re-synchronization and, consequently, improvement of cardiometabolic health.

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Identification of Novel Neurocircuitry Through Which Leptin Targets Multiple Inputs to the Dopamine System to Reduce Food Reward Seeking

Cited by 23 publications

References 48 publications

Neural Mechanism of Hunger-gated Food-seeking and Evaluating

Neural Mechanism of Hunger-gated Food-seeking and Evaluating

Leptin Receptor Expressing Neurons in the Substantia Nigra Regulate Locomotion, and in The Ventral Tegmental Area Motivation and Feeding

Chrono-communication and cardiometabolic health: The intrinsic relationship and therapeutic nutritional promises

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