Leptin Acts via Leptin Receptor-Expressing Lateral Hypothalamic Neurons to Modulate the Mesolimbic Dopamine System and Suppress Feeding

Leinninger, Gina M.; Jo, Young Hwan; Leshan, Rebecca L.; Louis, Gwendolyn W.; Yang, Hongyan; Barrera, Jason G.; Wilson, Hilary; Opland, Darren M.; Faouzi, Miro; Gong, Yusong; Jones, Justin C.; Rhodes, Christopher J.; Chua, Streamson C.; Diano, Sabrina; Horváth, Tamas L.; Seeley, Randy J.; Becker, Jill B.; Münzberg, Heike; Myers, Martin G.

doi:10.1016/j.cmet.2009.06.011

Cited by 368 publications

(451 citation statements)

References 46 publications

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“…31, 32). We also found that the GAD65 LH cells are distinct from the previously studied LH neurons expressing neuropeptide Y (NPY) or leptin receptor (33,34) (Fig. S2 A and B).…”

Section: Discussionmentioning

confidence: 57%

Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice

Kosse

Schöne

Bracey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Damage to the lateral hypothalamus (LH) causes profound physical inactivity in mammals. Several molecularly distinct types of LH neurons have been identified, including orexin cells and glutamic acid decarboxylase 65 (GAD65) cells, but their interplay in orchestrating physical activity is not fully understood. Here, using optogenetic circuit analysis and cell type-specific deep-brain recordings in behaving mice, we show that orexin cell activation rapidly recruits GAD65 LH neurons. We demonstrate that internally initiated GAD65 LH cell bursts precede and accompany spontaneous running bouts, that selective chemogenetic silencing of natural GAD65 LH cell activity depresses voluntary locomotion, and that GAD65 LH cell overactivation leads to hyperlocomotion. These results thus identify a molecularly distinct, orexin-activated LH submodule that governs physical activity in mice.T he lateral hypothalamus (LH) is thought to provide an essential drive for diverse vital behaviors, including locomotion. Peri-LH lesions in mammals disrupt context-appropriate physical activity, and are associated with the human disorder encephalitis lethargica, which has been noted to make humans "sit motionless. . .all day" (1-6). The LH is not a homogeneous entity, but contains many molecularly distinct classes of neurons that are thought to have different physiological roles (7). However, the interrelations of distinct LH cell classes in computing and driving context-appropriate physical activity are not fully understood.For example, LH neurons expressing orexins/hypocretins (8, 9) become activated in diverse stressful contexts, including acute auditory stimulation, hypoglycemia, hypercapnia, and physical capture (3, 9-13). Orexin LH cell activity may thus represent an important input variable for computing context-appropriate locomotor outputs (3,14), and orexin peptides have been proposed to increase arousal and locomotion by actions on extrahypothalamic projections to areas such as the locus coeruleus (15, 16). However, hypoactivity phenotypes caused by orexin LH cell deletion are milder than the hypoactivity phenotypes caused by broader LH lesions (1-3, 5, 12, 13, 17-19), whereas melanin-concentrating hormone LH (MCH LH ) cell deletion causes hyperactivity, implying that MCH LH cells suppress locomotion (20). These findings suggest that additional drivers of physical activity may exist in the LH.It was recently found that LH neurons expressing glutamic acid decarboxylase 65 (GAD65) are distinct from orexin and MCH neurons (21). We hypothesized that these cells may be a source of natural LH signals underlying normal levels of physical activity. Here, we investigate this hypothesis by using a combination of cell type-specific manipulation and recording techniques. We find that GAD65 LH cells operate as a stress-and orexin-activated LH module whose physiological activity is essential for normal locomotion, and whose hyperactivity causes hyperlocomotion. ResultsOrexin and Stress Rapidly Recruit GAD65 LH Neurons. To examine whether orex...

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“…31, 32). We also found that the GAD65 LH cells are distinct from the previously studied LH neurons expressing neuropeptide Y (NPY) or leptin receptor (33,34) (Fig. S2 A and B).…”

Section: Discussionmentioning

confidence: 57%

Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice

Kosse

Schöne

Bracey

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Most studies focus on hypothalamic LepRb signaling to explain leptin's effects on food intake and BW regulation (eg arcuate nucleus, LH, VMH) (Balthasar et al, 2004;Dhillon et al, 2006;Leinninger et al, 2009). However, recent findings strongly suggest that leptin's contribution to energy balance control is mediated by endogenous signaling that is anatomically distributed (Grill, 2010) across multiple brain regions that include the hindbrain (eg nucleus tractus solitarius (NTS) (Hayes et al, 2010)) and midbrain (eg ventral tegmental area (VTA) (Fulton et al, 2006;Hommel et al, 2006;Morton et al, 2009)) nuclei.…”

Section: Discussionmentioning

confidence: 99%

“…The importance of leptin signaling in the hypothalamus (Balthasar et al, 2004;Dhillon et al, 2006;Leinninger et al, 2009) and the caudal brainstem (Grill et al, 2002;Huo et al, 2007;Hayes et al, 2010) is established for the homeostatic or need-based control of food intake. However, given that the excessive food intake that contributes to human obesity is generally not driven by metabolic need, it is critical to examine and better define the neural basis of nonhomeostatic controls on food intake.…”

Section: Introductionmentioning

confidence: 99%

Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Kanoski

Hayes

Greenwald

et al. 2011

Neuropsychopharmacol

132

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The increase in obesity prevalence highlights the need for a more comprehensive understanding of the neural systems controlling food intake; one that extends beyond food intake driven by metabolic need and considers that driven by higher-order cognitive factors. The hippocampus, a brain structure involved in learning and memory function, has recently been linked with food intake control. Here we examine whether administration of the adiposity hormone leptin to the dorsal and ventral sub-regions of the hippocampus influences food intake and memory for food. Leptin (0.1 mg) delivered bilaterally to the ventral hippocampus suppressed food intake and body weight measured 24 h after administration; a higher dose (0.4 mg) was needed to suppress intake following dorsal hippocampal delivery. Leptin administration to the ventral but not dorsal hippocampus blocked the expression of a conditioned place preference for food and increased the latency to run for food in an operant runway paradigm. Additionally, ventral but not dorsal hippocampal leptin delivery suppressed memory consolidation for the spatial location of food, whereas hippocampal leptin delivery had no effect on memory consolidation in a non-spatial appetitive response paradigm. Collectively these findings indicate that ventral hippocampal leptin signaling contributes to the inhibition of food-related memories elicited by contextual stimuli. To conclude, the results support a role for hippocampal leptin signaling in the control of food intake and food-related memory processing.

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“…During fasting, there is marked upregulation of several hypothalamic orexigenic genes, including agouti-related protein (Agrp), neuropeptide Y (Npy), melanin-concentrating hormone (Mch), and Orexin. In contrast to the lateral hypothalamic MCH-and orexin-expressing neurons (Leinninger et al, 2009), AGRPexpressing neurons possess functional leptin receptors and are direct leptin targets (Kaelin et al, 2006;van de Wall et al, 2008;Olofsson et al, 2013). Accordingly, the fasting-induced increase in Agrp expression can be prevented by leptin treatment (Ebihara et al, 1999;Mizuno and Mobbs, 1999;Wilson et al, 1999;Korner et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Coordinated Regulation of Hepatic Energy Stores by Leptin and Hypothalamic Agouti-Related Protein

Warne

Varonin

Nielsen

et al. 2013

Journal of Neuroscience

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Like obesity, prolonged food deprivation induces severe hepatic steatosis; however, the functional significance of this phenomenon is not well understood. In this study, we show that the fall in plasma leptin concentration during fasting is required for the development of hepatic steatosis in mice. Removal of leptin receptors from AGRP neurons diminishes fasting-induced hepatic steatosis. Furthermore, the suppressive effects of leptin on fasting-induced hepatic steatosis are absent in mice lacking the gene encoding agouti-related protein (Agrp), suggesting that this function of leptin is mediated by AGRP. Prolonged fasting leads to suppression of hepatic sympathetic activity, increased expression of acyl CoA:diacylglycerol acyltransferase-2 in the liver, and elevation of hepatic triglyceride content and all of these effects are blunted in the absence of AGRP. AGRP deficiency, despite having no effects on feeding or body adiposity in the free-fed state, impairs triglyceride and ketone body release from the liver during prolonged fasting. Furthermore, reducing CNS Agrp expression in wild-type mice by RNAi protected against the development of hepatic steatosis not only during starvation, but also in response to consumption of a high-fat diet. These findings identify the leptin-AGRP circuit as a critical modulator of hepatic triglyceride stores in starvation and suggest a vital role for this circuit in sustaining the supply of energy from the liver to extrahepatic tissues during periods of prolonged food deprivation.

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Leptin Acts via Leptin Receptor-Expressing Lateral Hypothalamic Neurons to Modulate the Mesolimbic Dopamine System and Suppress Feeding

Cited by 368 publications

References 46 publications

Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice

Orexin-driven GAD65 network of the lateral hypothalamus sets physical activity in mice

Hippocampal Leptin Signaling Reduces Food Intake and Modulates Food-Related Memory Processing

Coordinated Regulation of Hepatic Energy Stores by Leptin and Hypothalamic Agouti-Related Protein

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