Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood–brain barrier

Banks, William A.; Burney, Basil O.; Robinson, Sandra

doi:10.1016/j.peptides.2008.07.001

Cited by 136 publications

(108 citation statements)

References 21 publications

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“…Although we cannot exclude a role for additional receptor-mediated transport processes in the ARH, no specific ghrelin uptake mechanisms could be identified in the murine BBB (18), and the rate of transport of ghrelin across the BBB was much lower when studied by brain perfusion vs. i.v. injection (32). Although systemic administration of ghrelin has previously been shown to induce hypothalamic c-fos expression (17), the current studies demonstrate sensing of hormone by ARH neurons over timescales (5 vs. 30 min) that are more compatible with the acute orexigenic effects of ghrelin on food intake (15).…”

Section: Discussionmentioning

confidence: 48%

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Schaeffer

Langlet

Lafont

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

268

198

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To maintain homeostasis, hypothalamic neurons in the arcuate nucleus must dynamically sense and integrate a multitude of peripheral signals. Blood-borne molecules must therefore be able to circumvent the tightly sealed vasculature of the blood-brain barrier to rapidly access their target neurons. However, how information encoded by circulating appetite-modifying hormones is conveyed to central hypothalamic neurons remains largely unexplored. Using in vivo multiphoton microscopy together with fluorescently labeled ligands, we demonstrate that circulating ghrelin, a versatile regulator of energy expenditure and feeding behavior, rapidly binds neurons in the vicinity of fenestrated capillaries, and that the number of labeled cell bodies varies with feeding status. Thus, by virtue of its vascular connections, the hypothalamus is able to directly sense peripheral signals, modifying energy status accordingly.hormone diffusion | in vivo imaging | median eminence | metabolism C ontinuous integration of peripheral signals by neurons belonging to the arcuate nucleus of the hypothalamus (ARH) is critical for central regulation of energy balance and neuroendocrine function (1). To dynamically report alterations to homeostasis and ensure an appropriate neuronal response, blood-borne factors such as hormones must rapidly access the central nervous system (CNS). This is particularly evident in the case of food intake, which is regulated by a plethora of circulating satiety signals (2) whose levels fluctuate in an ultradian manner. Despite this, it remains unclear how key energy status-signaling hormones such as ghrelin can be rapidly sensed by target neurons to alter feeding responses (3). Elucidation of the mechanisms underlying molecule entry into the brain is important for understanding not only normal maintenance of homeostasis but also how this is perturbed during common pathologies such as obesity and diabetes (4, 5).Although molecule transport mechanisms within the ARH are poorly characterized, they likely assume one of two forms. First, chronic feedback may be accomplished by uptake of circulating molecules into the ARH via saturable receptor-mediated transport at the level of the choroid plexus and/or bloodbrain barrier (BBB) (6-9). Second, the ARH is morphologically located in close apposition to the median eminence (ME), a circumventricular organ composed of fenestrated capillaries. Because these vessels project toward the ventromedial ARH (vmARH), they could represent a direct vascular input for passive diffusion of peripheral molecules into the hypothalamus (10-13). So far, study of the functional importance of fenestrated capillaries in molecule entry into the metabolic brain has been impeded by lack of appropriate tools.To evaluate the role of fenestrated ME/ARH capillaries in rapid detection of peripheral signals by the hypothalamus, we used a recently developed in vivo imaging approach to visualize in real time the extravasation of fluorescent molecules (14). Ghrelin was chosen as a candidate hormone because i...

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Section: Discussionmentioning

confidence: 48%

Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons

Schaeffer

Langlet

Lafont

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

268

198

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“…Studies have assessed the role of triglycerides on the transport of peptides across the BBB, [84][85][86] focusing on peptides which are important in metabolic syndrome and obesity. These studies examined transport in lean and diet-induced obese mice under normal, fasting, and starved conditions for insulin, leptin, and ghrelin, three substances shown to have cognitive effects.…”

Section: Triglycerides Alter Insulin and Other Peptide Uptake To The mentioning

confidence: 99%

“…Similar results have been observed with ghrelin, where its transport across the BBB was decreased with obesity and increased with triglycerides. 86 Ghrelin is also known to have an effect on cognition. 87 Triglycerides do not enhance all peptide transport across the BBB.…”

Section: Triglycerides Alter Insulin and Other Peptide Uptake To The mentioning

confidence: 99%

Insulin resistance, dyslipidemia, and apolipoprotein E interactions as mechanisms in cognitive impairment and Alzheimer's disease

Salameh

Rhea

Banks

et al. 2016

Exp Biol Med (Maywood)

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An increased risk for Alzheimer's disease is associated with dyslipidemia and insulin resistance. A separate literature shows the genetic risk for developing Alzheimer's disease is strongly correlated to the presence of the E4 isoform of the apolipoprotein E carrier protein. Understanding how apolipoprotein E carrier protein, lipids, amyloid b peptides, glucose, central nervous system insulin, and peripheral insulin interact with one another in Alzheimer's disease is an area of increasing interest. Here, we will review the evidence relating apolipoprotein E carrier protein, lipids, and insulin action to Alzheimer's disease and Ab peptides and then propose mechanisms as to how these factors might interact with one another to impair cognition and promote Alzheimer's disease.

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“…Moreover, serum factors and physiological states affect the ghrelin gene products across the blood-brain barrier. First, obesity and old age lost the ability to transport intravenous human acyl ghrelin across the blood-brain barrier, resulting in an inverse relationship between body weight and acyl ghrelin blood-brain barrier permeability (Banks et al, 2008). Second, serum triglycerides promoted transport of intravenous acyl ghrelin across the blood-brain barrier (Banks et al, 2008).…”

Section: Interactions Between Ghrelin Gene Products and The Blood-mentioning

confidence: 99%