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

Kleinert, Maximilian; Kotzbeck, Petra; Altendorfer‐Kroath, Thomas; Birngruber, Thomas; Tschöp, Matthias H.; Clemmensen, Christoffer

doi:10.1016/j.molmet.2018.04.008

Cited by 22 publications

(16 citation statements)

References 30 publications

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“…Accordingly, we did not evaluate the ratio of leptin entering the brain in relation to the levels in circulation. Our data are nonetheless in agreement with a very recent report on unchanged leptin BBB transport kinetics in mice fed chow or two weeks of HFD, which was built upon a novel micro-perfusion technique and the measurement of MBH leptin over a timeframe of 6 h [40].…”

Section: Discussionsupporting

confidence: 92%

Fluorescent blood–brain barrier tracing shows intact leptin transport in obese mice

et al. 2018

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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.

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Section: Discussionsupporting

confidence: 92%

Fluorescent blood–brain barrier tracing shows intact leptin transport in obese mice

et al. 2018

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“…Our results stand in contrast with recent reports in rodents suggesting that impaired transport of leptin in the hypothalamus does not precede diet‐induced obesity and that leptin receptor‐mediated transport across the blood‐brain barrier at the level of cerebral vessels and the blood‐CSF barrier at the choroid plexus is not critical for homeostatic feeding . However, the study of Kleinert et al focused on leptin actions in response to the administration of pharmacological doses of exogenous leptin and could not conclude about the transport dynamics of endogenous blood‐borne leptin across the blood‐CSF barrier that may involve tanycytic shuttles , which remained intact in the study by Di Spiezio et al .…”

Section: Discussioncontrasting

confidence: 99%

Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs

Chmielewski

Hübert

Descamps

et al. 2019

Obesity

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Objective A minipig model was employed to explore the changes in endogenous leptin transport into the central nervous system and in hypothalamic sensitivity to exogenous leptin when individuals are placed on high‐fat diet (HFD) compared with standard diet. Methods Serum and cerebrospinal fluid (CSF) leptin concentrations during 10 weeks of HFD versus standard diet and exogenous leptin‐induced STAT3 phosphorylation in the hypothalamus of minipigs were assessed, and the hypothalamic leptin‐sensitive cells were characterized by immunofluorescence. Results The efficiency of the passage of endogenous blood‐borne leptin into the CSF (measured as the log [CSF:serum leptin ratio]) decreased over time in minipigs fed a HFD (β = –0.04 ± 0.005 per kilogram of weight gain in HFD; P < 0.0001), while it remained stable in minipigs fed a standard diet. However, the ability of peripherally administered leptin to activate its receptor in hypothalamic neurons was preserved in obese minipigs at 10 weeks of HFD. Conclusions Together, these data are consistent with the existence of an early‐onset tranport deficiency for endogenous circulating leptin into the brain in individuals developing obesity, preceding the acquisition of hypothalamic leptin resistance. Although additional studies are required to identify the underlying mechanisms, our study paves the way for the development of new preclinical pharmacological models targeting the restoration of the shuttling of peripheral leptin into the central nervous system to manage obesity.

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“…Moreover, oral simvastatin treatment abolished the higher leptin expression in RVLM, pointing to a permissive role of dyslipidemia in brain uptake of leptin. Leptin has been shown to be transported across the blood-brain barrier to the brain in mice fed high fat diet [61], and the increase in brain leptin level inhibits AMPK phosphorylation [62]. In addition, leptin receptors are colocalized with AT 1A R in brain tissue [63].…”

Section: Discussionmentioning

confidence: 99%

Anomalous AMPK-regulated angiotensin AT1R expression and SIRT1-mediated mitochondrial biogenesis at RVLM in hypertension programming of offspring to maternal high fructose exposure

Chao

Tsai

et al. 2020

J Biomed Sci

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Background: Tissue oxidative stress, sympathetic activation and nutrient sensing signals are closely related to adult hypertension of fetal origin, although their interactions in hypertension programming remain unclear. Based on a maternal high-fructose diet (HFD) model of programmed hypertension, we tested the hypothesis that dysfunction of AMP-activated protein kinase (AMPK)-regulated angiotensin type 1 receptor (AT 1 R) expression and sirtuin1 (SIRT1)-dependent mitochondrial biogenesis contribute to tissue oxidative stress and sympathoexcitation in programmed hypertension of young offspring. Methods: Pregnant female rats were randomly assigned to receive normal diet (ND) or HFD (60% fructose) chow during pregnancy and lactation. Both ND and HFD offspring returned to ND chow after weaning, and blood pressure (BP) was monitored from age 6 to 12 weeks. At age of 8 weeks, ND and HFD offspring received oral administration of simvastatin or metformin; or brain microinfusion of losartan. BP was monitored under conscious condition by the tail-cuff method. Nutrient sensing molecules, AT 1 R, subunits of NADPH oxidase, mitochondrial biogenesis markers in rostral ventrolateral medulla (RVLM) were measured by Western blot analyses. RVLM oxidative stress was measured by fluorescent probe dihydroethidium and lipid peroxidation by malondialdehyde assay. Mitochondrial DNA copy number was determined by quantitative real-time polymerase chain reaction.

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

Cited by 22 publications

References 30 publications

Fluorescent blood–brain barrier tracing shows intact leptin transport in obese mice

Fluorescent blood–brain barrier tracing shows intact leptin transport in obese mice

Preclinical Assessment of Leptin Transport into the Cerebrospinal Fluid in Diet‐Induced Obese Minipigs

Anomalous AMPK-regulated angiotensin AT1R expression and SIRT1-mediated mitochondrial biogenesis at RVLM in hypertension programming of offspring to maternal high fructose exposure

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