Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance

Brown, Juliette A.; Bugescu, Raluca; Mayer, Thomas A.; Gata-Garcia, Adriana; Kurt, Gizem; Woodworth, Hillary L.; Leinninger, Gina M.

doi:10.1210/en.2017-00122

Cited by 50 publications

(49 citation statements)

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“…Studies across species were limited by the inability to easily identify Nts-expressing cells, but the recent development of Nts Cre mice enables the facile detection and manipulation of mouse Nts neurons using Cre-Lox technology. Using these mice we have identified a large population of Nts neurons in the LHA that project to the VTA, consistent with the prior afferent mapping done in rats, and manipulation of these LHA Nts neurons reveals their crucial contributions to motivated behavior and energy balance (Brown et al, 2017; Leinninger et al, 2011; Opland et al, 2013; Patterson et al, 2015; Woodworth et al, 2017b). The LHA may be just one of several sites by which Nts orchestrates distinct behavioral responses in the mouse VTA, thus it will be important to define all Nts afferents to the VTA and test their roles individually.…”

Section: Introductionsupporting

confidence: 81%

“…Nts has subsequently been identified throughout the brain (Beck et al, 1989; Carraway and Leeman, 1976; Jennes et al, 1982; Kitabgi et al, 1990; Uhl et al, 1979) and has been implicated in regulating a diverse repertoire of physiology and motivated behaviors including feeding, locomotor activity, social behavior, analgesia, sleep, and response to addictive drugs (Boules et al, 2011; Brown et al, 2017; Cape et al, 2000; Demeule et al, 2014; Ferraro et al, 2016; Fitzpatrick et al, 2012; Gammie et al, 2009; Merullo et al, 2015b; Smith et al, 2012). Nts may direct certain behaviors via actions in the ventral tegmental area (VTA), based on findings that different types of VTA neurons orchestrate distinct goal-directed behaviors (Lammel et al, 2012; Stamatakis et al, 2013; van Zessen et al, 2012), and that a specific subset of VTA neurons expresses neurotensin receptor-1 (Woodworth et al, 2017a).…”

Section: Introductionmentioning

confidence: 99%

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Determination of neurotensin projections to the ventral tegmental area in mice

et al. 2018

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Pharmacologic treatment with the neuropeptide neurotensin (Nts) modifies motivated behaviors such as feeding, locomotor activity, and reproduction. Dopamine (DA) neurons of the ventral tegmental area (VTA) control these behaviors, and Nts directly modulates the activity of DA neurons via Nts receptor-1. While Nts sources to the VTA have been described in starlings and rats, the endogenous sources of Nts to the VTA of mice remain incompletely understood, impeding determination of which Nts circuits orchestrate specific behaviors in this model. To overcome this obstacle we injected the retrograde tracer Fluoro-Gold into the VTA of mice that express GFP in Nts neurons. Identification of GFP-Nts cells that accumulate Fluoro-Gold revealed the Nts afferents to the VTA in mice. Similar to rats, most Nts afferents to the VTA of mice arise from the medial and lateral preoptic areas (POA) and the lateral hypothalamic area (LHA), brain regions that are critical for coordination of feeding and reproduction. Additionally, the VTA receives dense input from Nts neurons in the nucleus accumbens shell (NAsh) of mice, and minor Nts projections from the amygdala and periaqueductal gray area. Collectively, our data reveal multiple populations of Nts neurons that provide direct afferents to the VTA and which may regulate specific aspects of motivated behavior. This work lays the foundation for understanding endogenous Nts actions in the VTA, and how circuit-specific Nts modulation may be useful to correct motivational and affective deficits in neuropsychiatric disease.

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Section: Introductionsupporting

confidence: 81%

Section: Introductionmentioning

confidence: 99%

Determination of neurotensin projections to the ventral tegmental area in mice

et al. 2018

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“…LHA Nts neurons release Nts to target regions including the VTA, where VTA NtsR1 neurons contain DA (Brown et al, 2017; Patterson et al, 2015; Woodworth et al, 2017). Since VTA DA signaling modifies the motivation to work for food rewards (e.g.…”

Section: Resultsmentioning

confidence: 99%

“…The large population of LHA Nts neurons is distinct from orexigenic melanin-concentrating hormone or orexin/hypocretin neurons (Brown et al, 2017), and although some LHA Nts neurons co-express GABA (Jennings et al, 2015; Patterson et al, 2015), they but do not provoke the voracious feeding response that occurs with activation of all LHA GABA neurons (Jennings et al, 2013; Jennings et al, 2015; Navarro et al, 2016; Nieh et al, 2015). Instead, LHA Nts neurons are physiologically activated by signals that suppress feeding, such as dehydration anorexia (Watts and Sanchez-Watts, 2007) or the appetite-suppressing hormone, leptin (Leinninger et al, 2011).…”

mentioning

confidence: 99%

“…Instead, LHA Nts neurons are physiologically activated by signals that suppress feeding, such as dehydration anorexia (Watts and Sanchez-Watts, 2007) or the appetite-suppressing hormone, leptin (Leinninger et al, 2011). However, only 15% of LHA Nts neurons mediate leptin action (Brown et al, 2017; Leinninger et al, 2011), yet the overall role of the large population of LHA Nts neurons, and Nts signaling from them, is unclear. Since LHA Nts neurons release Nts to the VTA, where NtsR1-expressing dopamine (DA) neurons have been implicated in coordinating feeding and locomotor activity (Opland et al, 2013; Patterson et al, 2015; Woodworth et al, 2017), LHA Nts neurons might support NtsR1 and/or DA-mediated weight loss behaviors.…”

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confidence: 99%

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Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

et al. 2017

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SUMMARY The central mechanism by which neurotensin (Nts) potentiates weight loss has remained elusive. We leveraged chemogenetics to reveal that Nts-expressing neurons of the lateral hypothalamic area (LHA) promote weight loss in mice by increasing volitional activity and restraining food intake. Intriguingly, these dual weight loss behaviors are mediated by distinct signaling pathways: Nts action via NtsR1 is essential for the anorectic effect of the LHA Nts circuit, but not for regulation of locomotor or drinking behavior. Furthermore, although LHA Nts neurons cannot reduce intake of freely available obesogenic foods, they effectively restrain motivated feeding in hungry, weight-restricted animals. LHA Nts neurons are thus vital mediators of central Nts action, particularly in the face of negative energy balance. Enhanced action via LHA Nts neurons may therefore be useful to suppress the increased appetitive drive that occurs after lifestyle-mediated weight loss, and hence to prevent weight regain.

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Effects of GABA and Leptin Receptor‐Expressing Neurons in the Lateral Hypothalamus on Feeding, Locomotion, and Thermogenesis

Vrind

Rozeboom

Wolterink-Donselaar

et al. 2019

Obesity

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Objective The lateral hypothalamus (LH) is known for its role in feeding, and it also regulates other aspects of energy homeostasis. How genetically defined LH neuronal subpopulations mediate LH effects on energy homeostasis remains poorly understood. The behavioral effects of chemogenetically activating LH gamma‐aminobutyric acid (GABA) and the more selective population of LH GABA neurons that coexpress the leptin receptor (LepR) were compared. Methods LepR‐cre and VGAT‐cre mice were injected with AAV5‐hSyn‐DIO‐hM3DGq‐mCherry in the LH. The behavioral effects of LH GABA or LH LepR neuronal activation on feeding, locomotion, thermogenesis, and body weight were assessed. Results The activation of LH GABA neurons increased body temperature (P ≤ 0.008) and decreased body weight (P ≤ 0.01) despite decreased locomotor activity (P = 0.03) and transiently increased chow intake (P ≤ 0.009). Also, similar to other studies, this study found that activation of LH GABA neurons induced gnawing on both food and nonfood (P = 0.001) items. Activation of LH LepR neurons decreased body weight (P ≤ 0.01) and chow intake when presented on the cage floor (P ≤ 0.04) but not when presented in the cage top and increased locomotor activity (P = 0.002) and body temperature (P = 0.03). Conclusions LH LepR neurons are a subset of LH GABA neurons, and LH LepR activation more specifically regulates energy homeostasis to promote a negative energy balance.

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Loss of Action via Neurotensin-Leptin Receptor Neurons Disrupts Leptin and Ghrelin-Mediated Control of Energy Balance

Cited by 50 publications

References 54 publications

Determination of neurotensin projections to the ventral tegmental area in mice

Determination of neurotensin projections to the ventral tegmental area in mice

Lateral Hypothalamic Neurotensin Neurons Orchestrate Dual Weight Loss Behaviors via Distinct Mechanisms

Effects of GABA and Leptin Receptor‐Expressing Neurons in the Lateral Hypothalamus on Feeding, Locomotion, and Thermogenesis

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