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Differential Accessibility of Circulating Leptin to Individual Hypothalamic Sites

Division of Metabolism, Endocrinology, and Diabetes (M.F., R.L., M.B., T.H., J.J., H.M.), Departments of Medicine and Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, Michigan 48109; and Section of Integrative Physiology (M.B.), Department of Molecular Medicine and Surgery, Karolinska Institute, 171 77 Stockholm, Sweden

Address all correspondence and requests for reprints to: Heike Münzberg, Ph.D., Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, 1150 West Medical Center Drive, 5510D MSRB 1, Ann Arbor, Michigan 48109. E-mail: hmuenzbe{at}umich.edu.

Hypothalamic neurons expressing the long form of the leptin receptor (LRb) mediate important leptin actions. Although it has been suggested that leptin crosses the blood-brain barrier (BBB) via a specific transport system, we hypothesized the existence of a population of hypothalamic arcuate nucleus (ARC) neurons that senses leptin independently of this transport system. Indeed, endogenous circulating leptin results in detectable levels of baseline activated signal transducer and activator of transcription 3 (STAT3) phosphorylation in a population of ARC/LRb neurons, consistent with increased sensing of circulating leptin in these neurons compared with other LRb neurons. Furthermore, a population of ARC/LRb neurons that responds more rapidly and sensitively to circulating leptin compared with other hypothalamic LRb neurons detected by leptin activated phosphorylated STAT3. In addition, peripheral application of the BBB-impermeant retrograde tracer fluorogold revealed a population of ARC/LRb neurons that directly contact the circulation (e.g. via neuronal processes reaching outside the BBB). Taken together, these data suggest that a population of ARC/LRb neurons directly contacts the circulation and displays increased sensitivity to circulating leptin compared with neurons residing entirely behind the BBB elsewhere in the hypothalamus.

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