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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
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ABSTRACT

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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    • "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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    • "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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    • "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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