Cerebrospinal Fluid Levels of Leptin, Proopiomelanocortin, and Agouti-Related Protein in Human Pregnancy: Evidence for Leptin Resistance

Page-Wilson, Gabrielle; Reitman-Ivashkov, Elena; Meece, Kana; White, Anne; Rosenbaum, Michael; Smiley, Richard M.; Wardlaw, Sharon L.

doi:10.1210/jc.2012-2309

Cited by 35 publications

(37 citation statements)

References 43 publications

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“…Total POMC and BEP production were calculated by adding amounts of a neuropeptide in neuronal lysates to total released into the incubation medium. Neuropeptide assays were performed as described earlier (35,37). qPCR analysis.…”

Section: Discussionmentioning

confidence: 99%

Differentiation of hypothalamic-like neurons from human pluripotent stem cells

Wang¹,

Meece²,

Williams³

et al. 2015

J. Clin. Invest.

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125

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Section: Discussionmentioning

confidence: 99%

Differentiation of hypothalamic-like neurons from human pluripotent stem cells

Wang¹,

Meece²,

Williams³

et al. 2015

J. Clin. Invest.

Self Cite

113

125

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“…CSF and blood samples were centrifuged and stored at Ϫ80°C until assays were performed. Body composition was determined by dual-energy (21). Plasma leptin was measured using the same assay with appropriate dilution.…”

Section: Methodsmentioning

confidence: 99%

“…The physiology of this system has been well studied in rodents, but such studies are not possible in humans unless reliable biomarkers for brain leptin, POMC, and AgRP can be found. We have previously shown during pregnancy, despite hyperleptinemia, that elevated sOB-R may serve to decrease leptin transport into brain and that cerebrospinal fluid (CSF) levels of target neuropeptides are consistent with leptin resistance (21). However, little is known about CSF leptin and its relationship to sOB-R and to appropriate target neuropeptides in normal human subjects as a function of body weight and adiposity.…”

mentioning

confidence: 99%

Proopiomelanocortin, agouti-related protein, and leptin in human cerebrospinal fluid: correlations with body weight and adiposity

Page-Wilson

Meece

White

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Leptin and its neuronal targets, which produce proopiomelanocortin (POMC) and agouti-related protein (AgRP), regulate energy balance. This study characterized leptin, POMC, and AgRP in the cerebrospinal fluid (CSF) of 47 healthy human subjects, 23 lean and 24 overweight/ obese (OW/OB), as related to BMI, adiposity, plasma leptin, soluble leptin receptor (s-OB-R), and insulin. POMC was measured since the POMC prohormone is the predominant POMC peptide in CSF and correlates with hypothalamic POMC in rodents. Plasma AgRP was similarly characterized. CSF leptin was 83-fold lower than in plasma and correlated strongly with BMI, body fat, and insulin. The relative amount of leptin transported into CSF declined with increasing BMI, ranging from 4.5 to 0.52%, consistent with a saturable transport mechanism. CSF sOB-R was 78-fold lower than in plasma and correlated negatively with plasma and CSF leptin. CSF POMC was higher in lean vs. OW/OB subjects (P Ͻ 0.001) and correlated negatively with CSF leptin (r ϭ Ϫ0.60, P Ͻ 0.001) and with plasma leptin, insulin, BMI, and adiposity. CSF AgRP was not different in lean vs. OW/OB; however, plasma AgRP was higher in lean subjects (P ϭ 0.001) and correlated negatively with BMI, adiposity, leptin, insulin, and HOMA (P Ͻ 0.005). Thus, CSF measurements may provide useful biomarkers for brain leptin and POMC activity. The striking negative correlation between CSF leptin and POMC could be secondary to leptin resistance and/or neuronal changes associated with obesity but may also indicate that POMC plays a primary role in regulating body weight and adiposity. The role of plasma AgRP as a neuroendocrine biomarker deserves further study.proopiomelanocortin; agouti-related protein; leptin; cerebrospinal fluid THE ADIPOCYTE-DERIVED HORMONE leptin communicates levels of energy stores to key brain regions and elicits a host of neuronal responses that regulate energy balance (6,14). Leptin enters the brain by a saturable transport mechanism that involves, at least in part, a short isoform (Ob-Ra) of the leptin receptor found in the choroid plexus and cerebral microvessels (1, 9). Another circulating leptin receptor isoform, the soluble leptin receptor (sOB-R or Ob-Re), can also impact leptin transport into the brain. sOB-R may be derived from ectodomain shedding of the long form of the leptin receptor OB-Rb that is essential for leptin signaling (7). The physiological role of sOB-R is not yet completely understood. There is evidence that sOB-R functions as a leptin-binding protein that can inhibit leptin transport into brain but can also delay leptin clearance from the circulation (11, 33). High levels of sOB-R can block leptin's actions (26), but sOB-R overexpression results in a lean phenotype in mice (16). In humans, plasma sOB-R levels correlate negatively with BMI and increase with fasting(4, 34).The hypothalamic melanocortin system plays a critical role in responding to leptin, and disruption of this system at multiple levels causes obesity in humans and animals. This system consists of p...

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“…Podobne zjawisko występuje u ludzi -stężenie leptyny w osoczu ciężarnych kobiet wzrasta, osiągając maksimum w drugim trymestrze, natomiast w ostatnich tygodniach ciąży stężenie tego hormonu w osoczu zaczyna się obniżać, a jego najniższy poziom obserwowany jest po porodzie (22,23). Z przeprowadzonych niedawno badań wynika, że u kobiet w ciąży -pomimo podwyższonego stężenia leptyny w osoczu -stężenie tego hormonu w płynie mózgowo-rdzeniowym pozostaje na stałym, niskim poziomie (40). W czasie ciąży może zatem dochodzić do zmniejszenia wydajności transportu leptyny z krą-żenia do ośrodkowego układu nerwowego.…”

Section: Leptynooporność W Ciążyunclassified

“…Mechanizm ten występuje u myszy w ostatnim trymestrze ciąży, gdy leptyna łączy się w krążeniu z LEPRe, którego dodatkowym źródłem staje się wtedy łożysko (14). W przeprowadzonych niedawno badaniach z udziałem kobiet w ciąży również odnotowano podwyższone stężenie LEPRe w osoczu (40), co umożliwia zwiększone wiązanie leptyny przez tę formę receptora i powoduje wolniejszy transport tej adipokiny do płynu mózgowo-rdzeniowego. Ponadto w postaci związanej z LEPRe leptyna nie może akty-wować receptora błonowego LEPRb -jedynej izoformy receptora zdolnej do przekazywania sygnału tego hormonu w komórce.…”

Section: Mechanizmy Naturalnej Leptynoopornościunclassified

Physiological leptin resistance

Gogga¹,

Karbowska²,

Meissner³

et al. 2016

Medycyna Weterynaryjna

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Leptin is an adipose tissue-derived hormone whose circulating levels correlate with the amount of body fat stores. The main function of this adipokine is to regulate energy metabolism. By modulating the expression of orexigenic and anorexigenic neuropeptides in the hypothalamus, leptin reduces appetite. It also increases energy expenditure, contributing to the decrease of body fat and body weight. Mutations in the leptin receptor gene or prolonged consumption of a high-fat diet may impair leptin action, leading to leptin resistance. Resistance to leptin can also be an adaptive response that occurs in seasonal animals and in pregnant mammals. Reversible insensitivity to the satiety signal of leptin promotes hyperphagia, which is essential for animals living in dynamic environments and experiencing seasonal variation in food availability, since it allows them to forage intensely when food is abundant and accumulate fat reserves necessary to survive periods when food is scarce. Moreover, leptin resistance and subsequent hyperphagia develop during pregnancy in order to meet the energy needs of the growing fetus. Physiological leptin resistance may be due to impaired transport of leptin across the blood-brain barrier and/or to decreased sensitivity of the hypothalamus to this hormone resulting from an inhibition of leptin signalling in hypothalamic neurons. In pregnancy, an increased resistance to leptin action is also mediated by the binding of this adipokine to its placenta-derived soluble receptor. Reduced entry of leptin into the brain as well as alterations in the leptin signalling pathway in the hypothalamus leads to a transient decrease in sensitivity to this hormone preventing appetite suppression.

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Cerebrospinal Fluid Levels of Leptin, Proopiomelanocortin, and Agouti-Related Protein in Human Pregnancy: Evidence for Leptin Resistance

Abstract: These data demonstrate that despite peripheral hyperleptinemia, positive energy balance is achieved during pregnancy by a relative decrease in central leptin concentrations and resistance to leptin's effects on target neuropeptides that regulate energy balance.

Cited by 35 publications

References 43 publications

Differentiation of hypothalamic-like neurons from human pluripotent stem cells

Differentiation of hypothalamic-like neurons from human pluripotent stem cells

Proopiomelanocortin, agouti-related protein, and leptin in human cerebrospinal fluid: correlations with body weight and adiposity

Physiological leptin resistance

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