Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans

Schwartz, Michael W.; Peskind, Elaine R.; Raskind, Murray A.; Boyko, Edward J.; Porte, Daniel

doi:10.1038/nm0596-589

Cited by 920 publications

(591 citation statements)

References 15 publications

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“…The decrease in CSF:plasma leptin among obese patients is consistent with leptin resistance [31,32]. CSF leptin levels in children account for 5% of plasma levels, but unlike the plasma level, which is higher in girls, the CSF leptin concentration is similar in girls and boys [33].…”

Section: Discussionmentioning

confidence: 57%

“…Leptin concentrations in CSF are positively related to plasma level and BMI, but the CSF:plasma leptin ratio is reduced at the highest plasma leptin level, suggesting a saturable brain transport mechanism [31,32]. The decrease in CSF:plasma leptin among obese patients is consistent with leptin resistance [31,32].…”

Section: Discussionmentioning

confidence: 86%

“…The BBB could thus contribute to 'leptin resistance'; such a notion has been reported in obese subjects, where the increases in plasma leptin were not followed by parallel increases in the CSF leptin levels [31,32]. How the lack of a nocturnal increase in CSF leptin relates to the periodicity of energy balance and neuroendocrine axis is unknown [36].…”

Section: Discussionmentioning

confidence: 99%

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Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum

et al. 2007

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Aims/hypothesis Adiponectin is an adipocyte-derived secretory factor that is specifically produced in adipocytes. It exerts effects on energy homeostasis via peripheral and central mechanisms. However, it is not clear whether adiponectin crosses the blood-brain barrier in humans. In serum, adiponectin circulates in several different complexes, each of which has distinct functions. Here, we wanted to test whether adiponectin can be found in human cerebrospinal fluid (CSF) and whether specific adiponectin complexes are enriched in CSF compared with peripheral serum samples. We also wanted to establish whether there is a sex-related difference with regard to the distribution of adiponectin oligomers in CSF. Materials and methods We studied 22 subjects (11 men, 11 women) in this study. Their average BMI was 28.0± 4.7 kg/m 2 ; average age was 70±7 years. Results Analysis of total adiponectin revealed that adiponectin protein is present in human CSF at approximately 0.1% of serum concentration. The distribution of adiponectin oligomers differs considerably in CSF from that of serum within matched samples from the same patients. Only the adiponectin trimeric and low-molecular-mass hexameric complexes are found in CSF, with a bias towards the trimeric form in most patients. Male subjects have a higher CSF: serum ratio of total adiponectin (p<0.05; n=20) and have slightly higher trimer levels in serum and CSF than female subjects. Conclusions/interpretation We conclude that the adiponectin trimer is the predominant oligomer in human CSF.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

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Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum

et al. 2007

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“…Leptin transport across the bloodbrain barrier and/or the blood-cerebrospinal fluid barrier, any of the steps of the hormonal signal transduction cascade in the hypothalamus or even steps beyond the leptin-sensitive neurons are possible targets to be altered in leptin resistance states such as obesity and ageing. Alteration of leptin transport across the blood-brain barrier has been proposed to occur in obese humans [8,9], in New Zealand obese mice [10] and in diet-induced obese mice [11]. An impairment in the leptin signal transduction cascade has been shown in the old Fisher 344XBN rat [12,13].…”

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confidence: 99%

Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats

et al. 2002

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Aims/hypothesis. Ageing is associated with insulin and leptin resistance in mammals. These alterations might be caused by the increased adiposity associated with ageing, by ageing alone or both. We studied whether leptin resistance occurs at the central level in the Wistar rat and we aimed to discriminate between the effects of ageing from those of the increased adiposity associated with ageing. Methods. Leptin was infused intracerebroventricularly at a constant rate in young adult, old and old Wistar rats fasted for 3 months, using osmotic pumps. The effects on body weight, daily food intake, Lee index, adiposity and serum leptin values were analysed. The effect of food restriction on the expression of the long form of leptin receptor in the hypothalamus was also studied. Results. Leptin decreased daily food intake and body weight in young and old Wistar rats. With a dose of 10 µg/day similar responses were obtained in young and old rats but with a dose of 0.2 µg/day, only young rats showed decreases in these parameters. Foodrestriction in old rats lowered adiposity and serum leptin to values close to those of young rats, recovered responsiveness to i.c.v. administration of leptin at the dose of 0.2 µg/day and increased leptin receptor expression in the hypothalamus. Conclusion/interpretation. Our data show that old Wistar rats have a decreased response to leptin at the central level. Food-restriction recovers leptin responsiveness and increases leptin receptor in the hypothalamus suggesting that adiposity plays a key role in the development of leptin resistance associated with ageing. [Diabetologia (2002[Diabetologia ( ) 45:997-1003 Keywords Leptin, leptin-resistance, food-restriction, ageing, Wistar rat.

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“…Although leptin can be delivered in suggested that leptin enters the brain by a transport systhis way, the treatment is compromised by its short durtem that can be saturated. [2][3][4][5] Serum levels of leptin correation of action and the need for repetitive dosing. An late well with the body mass index of both children and alternative possible approach to recombinant protein adults, and bioactivity of leptin is influenced by its rate delivery is gene delivery.…”

Section: Introductionmentioning

confidence: 99%

Leptin gene therapy and daily protein administration: a comparative study in the ob/ob mouse

Morsy

Zhao

et al. 1998

Gene Ther

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We have compared the efficacy of daily injection of recomgiven as mean ± standard error of the mean.) Importantly, binant leptin protein (rh-leptin) with adenovirus-mediated rh-leptin and ex vivo-expressed Ad-leptin were equivalently delivery of the murine or human leptin gene (Ad-leptin) for active in a functional cell-based assay. The primary differtreatment of obesity in the obese (ob/ob) mouse model. ence in the two therapeutic approaches is the continuous We demonstrate an improved correction profile for obesity chronic secretion of leptin mediated by gene delivery, verand associated surrogate markers using the adenovirus sus the intermittent bolus delivery and rapid clearance of delivery method. Rate of weight loss and percentage satthe daily injection of rh-leptin protein. Thus, in vivo findings iety were significantly greater in the mice treated with Adsuggest that leptin effects are better achieved at lower leptin. These findings were associated with lower peak steady-state levels, a pharmacological feature attained serum leptin levels with Ad-leptin (22.9 ± 2.6 ng/ml for the here by gene therapy. These findings may have implihuman gene, and 48.9 ± 11.5 ng/ml for the murine gene) cations for the potential use of leptin in the treatment of compared to rh-leptin (385.2 ± 36.0 ng/ml). (Values are obesity.

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Cerebrospinal fluid leptin levels: Relationship to plasma levels and to adiposity in humans

Cited by 920 publications

References 15 publications

Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum

Adiponectin complexes in human cerebrospinal fluid: distinct complex distribution from serum

Long-term food restriction prevents ageing-associated central leptin resistance in wistar rats

Leptin gene therapy and daily protein administration: a comparative study in the ob/ob mouse

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