Abstract
Background/objectivesIndividuals carrying loss-of-function gene mutations for the adipocyte hormone leptin are morbidly obese, but respond favorably to replacement therapy. Recombinant leptin is however largely ineffective for the vast majority of obese individuals due to leptin resistance. One theory underlying leptin resistance is impaired leptin transport across the blood–brain-barrier (BBB). Here, we aim to gain new insights into the mechanisms of leptin BBB transport, and its role in leptin resistance.MethodsWe developed a novel tool for visualizing leptin transport using infrared fluorescently labeled leptin, combined with tissue clearing and light-sheet fluorescence microscopy. We corroborated these data using western blotting.ResultsUsing 3D whole brain imaging, we display comparable leptin accumulation in circumventricular organs of lean and obese mice, predominantly in the choroid plexus (CP). Protein quantification revealed comparable leptin levels in microdissected mediobasal hypothalami (MBH) of lean and obese mice (p = 0.99). We further found increased leptin receptor expression in the CP (p = 0.025, p = 0.0002) and a trend toward elevated leptin protein levels in the MBH (p = 0.17, p = 0.078) of obese mice undergoing weight loss interventions by calorie restriction or exendin-4 treatment.ConclusionsOverall, our findings suggest a crucial role for the CP in controlling the transport of leptin into the cerebrospinal fluid and from there to target areas such as the MBH, potentially mediated via the leptin receptor. Similar leptin levels in circumventricular organs and the MBH of lean and obese mice further suggest intact leptin BBB transport in leptin resistant mice.
Highlights
Maintenance of energy homeostasis is the keystone in preventing obesity and the metabolic syndrome
Several cell types such as pericytes and astrocytes contribute to the architecture and function of the blood–brain barrier (BBB), which protects the brain from neurotoxins while governing the passive diffusion of gases and hydrophobic molecules as well as the active transport of hydrophilic nutrients, amino acids and large-scale peptide hormones [2, 3]
Calorie restricted (CR) mice were restricted to the average food intake of the exendin-4 (EX4) group and EX4 treated animals were subjected to daily injections of exendin-4 (0.08 mg/kg) (Tocris biosciences, Bristol, UK) in the morning for up to 10 days
Summary
Maintenance of energy homeostasis is the keystone in preventing obesity and the metabolic syndrome. Direct innervation as well as indirect signaling via hormones allows for a feedback system back to the peripheral organs [1]. Several cell types such as pericytes and astrocytes contribute to the architecture and function of the blood–brain barrier (BBB), which protects the brain from neurotoxins while governing the passive diffusion of gases and hydrophobic molecules as well as the active transport of hydrophilic nutrients, amino acids and large-scale peptide hormones [2, 3]
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