Elsevier

Peptides

Volume 25, Issue 3, March 2004, Pages 331-338
Peptides

Review
The many lives of leptin

https://doi.org/10.1016/j.peptides.2004.02.014Get rights and content

Abstract

Leptin is a 16,000-Da protein which is secreted by fat but acts within the brain to regulate adiposity. Our Peptides Classic addressed the mystery of how such a large molecule could negotiate the blood–brain barrier (BBB), a structure which normally excludes proteins from the brain. We found that leptin was transported across the BBB by a saturable transport system. This finding was important to understanding how satiety-related peptides and proteins worked, but it was also important to the concept that the BBB is a regulatory interface important in brain–body communication. Obesity in humans and many animals is associated with a leptin resistant state rather than a leptin deficiency. Subsequent work has shown that a defect in the BBB transport of leptin is key in producing and reinforcing this state of resistance. Leptin is pluripotent and the concept of it being primarily an adipostat is being discarded for more encompassing views. Consideration of the BBB data would favor the view that ancestral levels of leptin were much lower than those currently considered normal and are consistent with leptin acting as a metabolic switch, informing the brain when fat reserves are adequate to direct energy expenditures towards activities other than seeking calories.

Section snippets

Introduction: life as an adipostat

In 1994, Zhang et al. [86] published a paper which solved an old mystery. It had long been known from parabiosis studies that the blood from rats with obesity induced by forced feeding, electrical stimulation, or some genetic lesions contained a substance which reduced food intake and fat mass in their partners [23], [48], [69]. Using modern molecular biology tools, Zhang et al. identified this substance to be Ob protein, now more widely known as leptin. Leptin is secreted from adipose tissue

A background of peptide and protein transport across the BBB

Our laboratory had a long-standing interest in the question of whether peptides or proteins could cross the BBB at the time leptin was discovered. Despite the majority of opinion against the idea that peptides could not cross, a small group of researchers persevered throughout the 1980s, examining the question, developing new tools, and refining analyses. Our review in 1985 stated the evidence gathered to that time that supported the idea that peptides could cross the BBB [11] and was in direct

Blood to brain passage: the pathways available to leptin

Of the various pathways by which peptides and proteins cross the BBB, two had been considered for leptin: saturable transport and entry into the CNS by way of the CVOs. Our manuscript addressed both of these pathways.

Small, lipid soluble substances can enter the CNS from the blood by diffusing through the membranes which comprise the BBB [67]. Even some of the smaller peptides can enter enough to affect brain function [10], [13]. But our manuscript confirmed that leptin, which is about 1/4th

Summary: the role of the BBB in the lives of leptin

Leptin must cross the BBB to act at the arcuate nucleus. It does so because a saturable transport system exits at the vascular BBB and choroid plexus. Failure of this transporter is a major contributor to the development of leptin resistance in obesity. In humans and diet-induced obesity of outbred rodents, BBB resistance likely precedes resistance at the arcuate nucleus. BBB resistance is acquired and to some extent reversible. The BBB transporter for leptin is regulated by a number of

Acknowledgements

Supported by VA merit review and R01 NS41863 and R01 AA12743.

References (88)

  • R.D Broadwell et al.

    Serum proteins bypass the blood-brain barrier for extracellular entry to the central nervous system

    Exp. Neurol.

    (1993)
  • J.F Caro et al.

    Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance

    Lancet

    (1996)
  • H Goiot et al.

    Antral mucosa expresses functional leptin receptors coupled to STAT-3 signaling, which is involved in the control of gastric secretions in the rat

    Gastroenterology

    (2001)
  • X.M Guan et al.

    Differential expression of mRNA for leptin receptor isoforms in the rat brain

    Mol. Cell. Endocrinol.

    (1997)
  • E.G Gutierrez et al.

    Murine tumor necrosis factor alpha is transported from blood to brain in the mouse

    J. Neuroimmunol.

    (1993)
  • A.J Kastin et al.

    Fasting, but not adrenalectomy, reduces transport of leptin into the brain

    Peptides

    (2000)
  • A.J Kastin et al.

    Decreased transport of leptin across the blood-brain barrier in rats lacking the short form of the leptin receptor

    Peptides

    (1999)
  • R.B Lynn et al.

    Autoradiographic localization of leptin binding in the choroid plexus of ob/ob and db/db mice

    Biochem. Biophys. Res. Commun.

    (1996)
  • L.M Maness et al.

    Periventricular penetration and disappearance of icv Tyr-MIF-1, DAMGO, tyrosine, and albumin

    Peptides

    (1996)
  • G.A Maresh et al.

    In vitro demonstration of a saturable transport system for leptin across the blood-brain barrier

    Life Sci.

    (2001)
  • G Pelletier et al.

    Radioautographic localization of radioactivity in rat brain after intracarotid injection of 125I-α-melanocyte-stimulating hormone

    Pharmacol. Biochem. Behav.

    (1975)
  • M Rethelyi

    Diffusional barrier around the hypothalamic arcuate nucleus in the rat

    Brain Res.

    (1984)
  • S Shioda et al.

    Immunohistochemical localization of leptin receptor in the rat brain

    Neurosci. Lett.

    (1998)
  • B.M Spiegelman et al.

    Adipogenesis and obesity: rounding out the big picture

    Cell

    (1996)
  • L.A Tartaglia et al.

    Identification and expression cloning of a leptin receptor, OB-R

    Cell

    (1995)
  • S.A Thomas et al.

    Leptin transport at the blood-cerebrospinal fluid barrier using the perfused sheep choroid plexus model

    Brain Res.

    (2001)
  • G.F.M Verhoeven et al.

    The syndromes of primary hormone resistance

    N. Engl. J. Med.

    (1979)
  • R.S Ahima et al.

    Leptin accelerates the onset of puberty in normal female mice

    J. Clin. Invest.

    (1997)
  • R.S Ahima et al.

    Role of leptin in the neuroendocrine response to feeding

    Nature

    (1996)
  • W.A Banks

    Is obesity a disease of the blood-brain barrier? Physiological, pathological, and evolutionary considerations

    Curr. Pharm. Design

    (2003)
  • W.A Banks et al.

    Serum leptin levels as a marker for a syndrome X-like condition in wild baboons

    J. Clin. Endocrinol. Metab.

    (2003)
  • W.A Banks et al.

    Partial saturation and regional variation in the blood to brain transport of leptin in normal weight mice

    Am. J. Physiol.

    (2000)
  • W.A Banks et al.

    Impaired transport of leptin across the blood-brain barrier in obesity is acquired and reversible

    Am. J. Physiol.

    (2003)
  • W.A Banks et al.

    Editorial review: peptide transport systems for opiates across the blood-brain barrier

    Am. J. Physiol.

    (1990)
  • W.A Banks et al.

    Strategies for the delivery of leptin to the CNS

    J. Drug Target.

    (2002)
  • W.A Banks et al.

    Serum leptin levels in wild and captive populations of baboons (Papio): implications for the ancestral role of leptin

    J. Clin. Endocrinol. Metab.

    (2001)
  • M Baratta

    Leptin: from a signal of adiposity to a hormonal mediator at peripheral tissues

    Med. Sci. Monitor

    (2003)
  • Begley DJ. Peptides and the blood-brain barrier. In: Bradbury MWB, editor. Handbook of experimental pharmacology....
  • C Bjorbaek et al.

    Expression of leptin receptor isoforms in rat brain microvessels

    Endocrinology

    (1998)
  • G.A Bray et al.

    Genetically transmitted obesity in rodents

    Physiol. Rev.

    (1971)
  • J Brownlees et al.

    Peptidases, peptides, and the mammalian blood-brain barrier

    J. Neurochem.

    (1993)
  • B Burguera et al.

    Obesity is associated with a decreased leptin transport across the blood-brain barrier in rats

    Diabetes

    (2000)
  • L.A Campfield et al.

    Recombinant mouse OB protein: evidence for a peripheral signal linking adiposity and central neural networks

    Science

    (1995)
  • G.Y Cao et al.

    Leptin receptors in the adrenal medulla of the rat

    Am. J. Physiol.

    (1997)
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    DOI of original article: 10.1016/0196-9781(96)00025-3.

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