Time-resolved hypothalamic open flow micro-perfusion reveals normal leptin transport across the blood–brain barrier in leptin resistant mice

Maximilian Kleinert,Petra Kotzbeck,Thomas Altendorfer-Kroath,Thomas Birngruber,Matthias H Tschöp,Christoffer Clemmensen

doi:10.1016/j.molmet.2018.04.008

Maximilian Kleinert, Petra Kotzbeck + Show 4 more

Open Access

https://doi.org/10.1016/j.molmet.2018.04.008

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Abstract

ObjectiveThe inability of leptin to suppress food intake in diet-induced obesity, sometimes referred to as leptin resistance, is associated with several distinct pathological hallmarks. One prevailing theory is that impaired transport of leptin across the blood–brain barrier (BBB) represents a molecular mechanism that triggers this phenomenon. Recent evidence, however, has challenged this notion, suggesting that leptin BBB transport is acquired during leptin resistance. MethodsTo resolve this debate, we utilized a novel cerebral Open Flow Microperfusion (cOFM) method to examine leptin BBB transport in male C57BL/6J mice, fed a chow diet or high fat diet (HFD) for 20 days. ResultsBasal plasma leptin levels were 3.8-fold higher in HFD-fed mice (p < 0.05). Leptin administration (2.5 mg/kg) elicited similar pharmacokinetic profiles of circulating leptin. However, while leptin reduced food intake by 20% over 22 h in chow-fed mice, it did not affect food intake in HFD-fed mice. In spite of this striking functional difference, hypothalamic leptin levels, as measured by cOFM, did not differ between chow-fed mice and HFD-fed mice following leptin administration. ConclusionsThese data suggest that leptin transport across the BBB is not impaired in non-obese leptin resistant mice and thus unlikely to play a direct role in the progression of pharmacological leptin resistance.

Highlights

Leptin is a 16 kDa hormone that is secreted from white adipocytes to signal satiety in the brain
Twenty days of high fat diet (HFD)-feeding induces functional leptin resistance Compared to chow-fed mice, HFD-fed mice did gain 1.7 g more bodyweight (p < 0.05) but did not reach an obese state by any definition (Figure 1A)
In contrast to its effect in chow-fed animals, leptin injection in HFD-fed mice had no effect on food intake or body-weight (Figure 1C)

Summary

Introduction

Leptin is a 16 kDa hormone that is secreted from white adipocytes to signal satiety in the brain It plays a critical role in the neuroendocrine regulation of body-weight [1e3]. One prevailing theory is that impaired transport of leptin across the bloode brain barrier (BBB) plays a central role to this blunted responsiveness to exogenous leptin e sometimes referred to as leptin resistance. The relative contribution and the sequential manifestation of these events reported to be associated with functional leptin resistance remain unclear Given this uncertainty, we took advantage of recent methodological advances to quantify leptin transport across the BBB in the early stages of dietinduced leptin resistance (i.e. the inability of exogenous leptin to suppress food intake). Cerebral Open Flow Microperfusion (cOFM) is a new in vivo technique that allows for continuous sampling of the interstitial fluid in brain tissue [16e18], enabling the time-resolved

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