Coppari, R. et al. The hypothalamic arcuate nucleus: a key site for mediating leptin's effects on glucose homeostasis and locomotor activity. Cell Metab. 1, 63-72

Department of Pathology & Cell Biology, Columbia University, New York, New York, United States
Cell Metabolism (Impact Factor: 17.57). 02/2005; 1(1):63-72. DOI: 10.1016/j.cmet.2004.12.004
Source: PubMed


Leptin is required for normal energy and glucose homeostasis. The hypothalamic arcuate nucleus (ARH) has been proposed as an important site of leptin action. To assess the physiological significance of leptin signaling in the ARH, we used mice homozygous for a FLPe-reactivatable, leptin receptor null allele (Lepr(neo/neo) mice). Similar to Lepr(db/db) mice, these mice are obese, hyperglycemic, hyperinsulinemic, infertile, and hypoactive. To selectively restore leptin signaling in the ARH, we generated an adeno-associated virus expressing FLPe-recombinase, which was delivered unilaterally into the hypothalamus using stereotaxic injections. We found that unilateral restoration of leptin signaling in the ARH of Lepr(neo/neo) mice leads to a modest decrease in body weight and food intake. In contrast, unilateral reactivation markedly improved hyperinsulinemia and normalized blood glucose levels and locomotor activity. These data demonstrate that leptin signaling in the ARH is sufficient for mediating leptin's effects on glucose homeostasis and locomotor activity.

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Available from: Masumi Ichinose
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    • "Few studies have investigated the mechanisms underlying the effects of leptin on physical activity. The hypoactivity of obese, LepR-deficient mice is corrected by restoration of LepR to the mediobasal hypothalamus (Coppari et al., 2005) or proopiomelanocortin neurons (Huo et al., 2009), underscoring the role of the hypothalamus in the actions of leptin to stimulate locomotor behavior. However, leptin suppression of physical activity when food is limited suggests the presence of distinct neural mechanisms. "
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    ABSTRACT: The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of running ("runner's high") are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food. Copyright © 2015 Elsevier Inc. All rights reserved.
    Full-text · Article · Aug 2015 · Cell metabolism
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    • "Young mice lacking the Ob-Rb in POMC and NPY/AgRP neurons exhibit hyperphagia, decreased energy expenditure and increased weight gain, which is partially attenuated by high levels of leptin, indicating that the absence of leptin action in NPY/AgRP and POMC neurons is partially compensated by other leptin-regulated pathways (van de Wall et al., 2008). Ob-Rb deficiency in POMC and AgRP neurons results in hyperinsulinemia (van de Wall et al., 2008) while rescuing Ob-Rb expression in Arc neurons of Ob-Rb deficient rodents partially normalizes glucose and insulin levels (Coppari et al., 2005), demonstrating the involvement of leptin in the regulation of glucose homeostasis and insulin levels. Of functional importance is that the activity of Arc POMC and NPY/AgRP neurons is also modulated via leptin-regulated projections originating in other hypothalamic nuclei. "
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    ABSTRACT: The anorexigenic hormone leptin plays an important role in the control of food intake and feeding-related behavior, for an important part through its action in the hypothalamus. The adipose-derived hormone modulates a complex network of several intercommunicating orexigenic and anorexigenic neuropeptides in the hypothalamus to reduce food intake and increase energy expenditure. In this review we present an updated overview of the functional role of leptin in respect to feeding and feeding-related behavior per distinct hypothalamic nuclei. In addition to the arcuate nucleus, which is a major leptin sensitive hub, leptin-responsive neurons in other hypothalamic nuclei, including the, dorsomedial-, ventromedial- and paraventricular nucleus and the lateral hypothalamic area, are direct targets of leptin. However, leptin also modulates hypothalamic neurons in an indirect manner, such as via the melanocortin system. The dissection of the complexity of leptin's action on the networks involved in energy balance is subject of recent and future studies. A full understanding of the role of hypothalamic leptin in the regulation of energy balance requires cell-specific manipulation using of conditional deletion and expression of leptin receptors. In addition, optogenetic and pharmacogenetic tools in combination with other pharmacological (such as the recent discovery of a leptin receptor antagonist) and neuronal tracing techniques to map the circuit, will be helpful to understand the role of leptin receptor expressing neurons. Better understanding of these circuits and the involvement of leptin could provide potential sites for therapeutic interventions in obesity and metabolic diseases characterized by dysregulation of energy balance.
    Full-text · Article · Jul 2014 · Journal of Chemical Neuroanatomy
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    • "Lesions in the medial basal hypothalamus (MBH), which includes ARC and the ventromedial hypothalamus (VMH), result in hyperphagia and extreme obesity [63] [64]. Restoration of leptin and LepRb activity in the MBH decreases this hyperphagia and obesity [65] [66]. VMH neurons have a role in satiety, sending excitatory inputs to POMC neurons in ARC that correlate with leptin levels [67] [68]. "
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    ABSTRACT: Receptors of leptin, the prototypical adipokine, are expressed throughout the cortex and several other areas of the brain. Although typically studied for its role in energy intake and expenditure, leptin plays a critical role in many other neurocognitive processes and interacts with various other hormones and neurotransmitters to perform these functions. Here, we review the literature on how leptin influences brain development, neural degradation, Alzheimer’s disease, psychiatric disorders, and more complicated cognitive functioning and feeding behaviors. We also discuss modulators of leptin and the leptin receptor as they relate to normal cognitive functioning and may mediate some of the actions of leptin in the brain. Although we are beginning to better understand the critical role leptin plays in normal cognitive functioning, there is much to be discovered.
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