Diurnal Patterns for Cortisol, Cortisone and Agouti-Related Protein in Human Cerebrospinal Fluid and Blood

Abstract Context Cortisol in blood has a robust circadian rhythm and exerts potent effects on energy balance that are mediated in part by central mechanisms. These interactions involve orexigenic agouti-related protein (AgRP) neurons that are stimulated by glucocorticoids. However, diurnal changes in brain or cerebrospinal fluid (CSF) cortisol and cortisone, which are interconverted by 11ß-HSD1, have not been characterized in humans. Objective To conduct a secondary analysis of existing samples to characterize diurnal changes in cortisol and cortisone in CSF and examine their relationships to changes in AgRP. Methods Stored CSF and plasma samples were obtained from 8 healthy subjects who served as controls for a sleep study. CSF was collected every 2h for 36h via indwelling lumbar catheter; plasma was collected every 2h. Results There was a diurnal rhythm for cortisol and cortisone in CSF that closely followed the plasma rhythm by 2 h with peak and nadir levels at 0900h and 0100h. The ratio of cortisol (active) to cortisone (inactive) in CSF was 48% higher at the peak versus nadir. There was a diurnal rhythm for AgRP in plasma that was out of phase with the cortisol rhythm. There was a less distinct diurnal rhythm for AgRP in CSF that oscillated with a similar phase as cortisol. Conclusions There is a robust diurnal rhythm for cortisol and cortisone in CSF. Diurnal changes were noted for AgRP that are related to the cortisol changes. It remains to be determined if AgRP mediates adverse metabolic effects associated with disruption of the cortisol circadian rhythm.

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Cerebrospinal fluid levels of insulin, leptin, and agouti-related protein in relation to BMI in pregnant women

Obesity ◽

10.1002/oby.21502 ◽

2016 ◽

Vol 24 (6) ◽

pp. 1299-1304 ◽

Cited By ~ 4

Author(s):

Carolina Gustavsson ◽

Ulrika Andersson Hall ◽

Aurimantas Pelanis ◽

Ove I. Karlsson ◽

Louise Andersson ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Pregnant Women ◽

Related Protein ◽

Cerebrospinal Fluid Levels ◽

Agouti Related Protein ◽

Fluid Levels

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

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2012-2309 ◽

2013 ◽

Vol 98 (1) ◽

pp. 264-271 ◽

Cited By ~ 25

Author(s):

Gabrielle Page-Wilson ◽

Elena Reitman-Ivashkov ◽

Kana Meece ◽

Anne White ◽

Michael Rosenbaum ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Leptin Resistance ◽

Related Protein ◽

Cerebrospinal Fluid Levels ◽

Human Pregnancy ◽

Agouti Related Protein ◽

Fluid Levels

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Diurnal Changes in Murine Spermatogenesis

Zeitschrift für Naturforschung C ◽

10.1515/znc-1994-7-820 ◽

1994 ◽

Vol 49 (7-8) ◽

pp. 522-525 ◽

Cited By ~ 2

Author(s):

Ursula Beate Hacker-Klom

Keyword(s):

Flow Cytometry ◽

Circadian Rhythm ◽

Dna Synthesis ◽

Diurnal Rhythm ◽

Synthesis Rate ◽

Diurnal Changes ◽

Nmri Mice

We analysed testicular samples of NMRI mice every 2 h of a day in order to determine whether there is a circadian rhythm in spermatogenetic activity. We used flow cytometry after staining the DNA with DAPI. The highest proportion of DNA synthesizing cells (mainly spermatogonia and preleptotene spermatocytes) was seen at 8 p.m. and especially at 10 p.m.; the lowest proportion was observed at 2 p.m. At 6 a.m., the percentage of round spermatids increased significantly, whereas the fraction of 4c-cells decreased at that time. Our results of a diurnal rhythm of spermatogenic DNA synthesis rate are in contrast to another publication of other authors (Oakberg and Crosswait, 1983)

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Cerebrospinal Fluid (CSF) Levels of Proopiomelanocortin (POMC) and Agouti-Related Protein (AgRP) in Human Pregnancy: Evidence for Leptin Resistance

10.1210/endo-meetings.2011.part3.p28.p3-242 ◽

2011 ◽

pp. P3-242-P3-242

Author(s):

Gabrielle Page-Wilson ◽

Elena Reitman-Ivashkov ◽

Kana Meece ◽

Anne White ◽

Michael Rosenbaum ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Leptin Resistance ◽

Related Protein ◽

Human Pregnancy ◽

Csf Levels ◽

Agouti Related Protein

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Signal Transducer and Activator of Transcription-3 Is Required in Hypothalamic Agouti-Related Protein/Neuropeptide Y Neurons for Normal Energy Homeostasis

Endocrinology ◽

10.1210/en.2007-0945 ◽

2008 ◽

Vol 149 (7) ◽

pp. 3346-3354 ◽

Cited By ~ 55

Author(s):

Lijie Gong ◽

Fayi Yao ◽

Kristin Hockman ◽

Henry H. Heng ◽

Gregory J. Morton ◽

...

Keyword(s):

Neuropeptide Y ◽

Energy Homeostasis ◽

Leptin Receptor ◽

Metabolic Effects ◽

Cytokine Signaling ◽

Mrna Levels ◽

Signal Transducer ◽

Related Protein ◽

Fat Cell ◽

Agouti Related Protein

Signal transducer and activator of transcription (Stat)-3 signals mediate many of the metabolic effects of the fat cell-derived hormone, leptin. In mice, brain-specific depletion of either the long form of the leptin receptor (Lepr) or Stat3 results in comparable obese phenotypes as does replacement of Lepr with an altered leptin receptor locus that codes for a Lepr unable to interact with Stat3. Among the multiple brain regions containing leptin-sensitive Stat3 sites, cells expressing feeding-related neuropeptides in the arcuate nucleus of the hypothalamus have received much of the focus. To determine the contribution to energy homeostasis of Stat3 expressed in agouti-related protein (Agrp)/neuropeptide Y (Npy) arcuate neurons, Stat3 was deleted specifically from these cells, and several metabolic indices were measured. It was found that deletion of Stat3 from Agrp/Npy neurons resulted in modest weight gain that was accounted for by increased adiposity. Agrp/Stat3-deficient mice also showed hyperleptinemia, and high-fat diet-induced hyperinsulinemia. Stat3 deletion in Agrp/Npy neurons also resulted in altered hypothalamic gene expression indicated by increased Npy mRNA and decreased induction of suppressor of cytokine signaling-3 in response to leptin. Agrp mRNA levels in the fed or fasted state were unaffected. Behaviorally, mice without Stat3 in Agrp/Npy neurons were mildly hyperphagic and hyporesponsive to leptin. We conclude that Stat3 in Agrp/Npy neurons is required for normal energy homeostasis, but Stat3 signaling in other brain areas also contributes to the regulation of energy homeostasis.

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

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00206.2015 ◽

2015 ◽

Vol 309 (5) ◽

pp. E458-E465 ◽

Cited By ~ 15

Author(s):

Gabrielle Page-Wilson ◽

Kana Meece ◽

Anne White ◽

Michael Rosenbaum ◽

Rudolph L. Leibel ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Body Weight ◽

Leptin Receptor ◽

Human Subjects ◽

Leptin Resistance ◽

Primary Role ◽

Related Protein ◽

Healthy Human ◽

Plasma Leptin ◽

Agouti Related Protein

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 < 0.001) and correlated negatively with CSF leptin ( r = −0.60, P < 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 = 0.001) and correlated negatively with BMI, adiposity, leptin, insulin, and HOMA ( P < 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.

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Diurnal Rhythm of Agouti-Related Protein and Its Relation to Corticosterone and Food Intake

Endocrinology ◽

10.1210/en.2002-220150 ◽

2002 ◽

Vol 143 (10) ◽

pp. 3905-3915 ◽

Cited By ~ 58

Author(s):

Xin-Yun Lu ◽

Kun-Ruey Shieh ◽

Mohamed Kabbaj ◽

Gregory S. Barsh ◽

Huda Akil ◽

...

Keyword(s):

Food Intake ◽

Diurnal Rhythm ◽

Related Protein ◽

Agouti Related Protein

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Effects of Estradiol on Cerebrospinal Fluid Levels of Agouti-Related Protein in Ovariectomized Rhesus Monkeys

Endocrinology ◽

10.1210/en.2009-0853 ◽

2010 ◽

Vol 151 (3) ◽

pp. 1002-1009 ◽

Cited By ~ 9

Author(s):

Ennian Xiao ◽

Andrea J. Kim ◽

Roxanne Dutia ◽

Irene Conwell ◽

Michel Ferin ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Full Length ◽

Biologically Active ◽

Melanocortin Receptor ◽

Leptin Resistance ◽

Related Protein ◽

Melanocortin System ◽

Estrogen Regulation ◽

Lumbar Cerebrospinal Fluid ◽

Agouti Related Protein

Hypothalamic proopiomelanocortin (POMC)-derived MSH peptides and the melanocortin receptor antagonist, agouti-related protein (AgRP), interact to regulate energy balance. Both POMC and AgRP neurons express estrogen receptors, but little is known about estrogen regulation of the melanocortin system in the primate. We have therefore examined the effects of physiological doses of estradiol (E2) on POMC and AgRP in lumbar cerebrospinal fluid (CSF) of ovariectomized monkeys. POMC prohormone was measured by ELISA. AgRP was measured by RIA (sensitive for the more biologically active C-terminal AgRP83-132 but also detects full-length AgRP) and by ELISA (measures primarily full length AgRP). In the first experiment, 14 animals were studied before and after 3 wk of E2. CSF POMC did not change, but AgRP(RIA) decreased from 7.9 ± 1.2 to 4.7 ± 1.2 fmol/ml after E2 (P = 0.03) and the POMC/AgRP(RIA) ratio increased from 4.2 ± 0.89 to 6.8 ± 1.04 (P = 0.04). AgRP(ELISA) did not change, but the ratio of AgRP(RIA) compared with AgRP(ELISA) was reduced after E2 (P = 0.02). In the second experiment, 11 animals were studied after 6 wk of E2, and similar changes were noted. The degree of AgRP(RIA) suppression with E2 was inversely related to body mass index (r = 0.569; P = 0.03). These results show for the first time that E2 suppresses AgRP(C-terminal) in CSF, increases the POMC to AgRP ratio, and may decrease AgRP processing, thus leading to increased melanocortin signaling. Furthermore, obesity was associated with resistance to the suppressive effects of E2 on AgRP, analogous to what is seen with obesity and leptin resistance.

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