Adiponectin Does Not Cross the Blood-Brain Barrier but Modifies Cytokine Expression of Brain Endothelial Cells

Abstract

Adiponectin has recently been reported to generate a negative energy balance by increasing energy expenditure. However, it is unclear whether such effects require the presence and direct action of the adiponectin protein in the central nervous system. In this study, neither radiolabeled nonglycosylated nor glycosylated globular adiponectin crossed the blood-brain barrier (BBB) in mice. In addition, adiponectin was not detectable in human cerebrospinal fluid using various established methods. Using murine cerebral microvessels, we demonstrated expression of adiponectin receptors, which are upregulated during fasting, in brain endothelium. Interestingly, treatment with adiponectin reduced secretion of the centrally active interleukin-6 from brain endothelial cells, a phenomenon that was paralleled by a similar trend of other proinflammatory cytokines. In summary, our data suggest that direct effects of endogenous adiponectin on central nervous system pathways are unlikely to exist. However, the identification of adiponectin receptors on brain endothelial cells and the finding of a modified secretion pattern of centrally active substances from BBB cells provides an alternate explanation as to how adiponectin may evoke effects on energy metabolism. Diabetes 55: [141][142][143][144][145][146][147] 2006 A diponectin is an adipocyte-specific protein, and its structure consists of an NH 2 -terminal collagenous domain and a COOH-terminal globular domain (1-6). Various studies have associated adiponectin with insulin sensitivity (7-10). In epidemiological studies, high levels of adiponectin were associated with a reduced diabetes and coronary heart disease risk (11-13).A growing body of evidence suggests that adiponectin directly affects energy balance by increasing thermogenesis (14). Recent studies in C57BL6 mice demonstrated that globular and full-length adiponectin decreases body weight after central or peripheral administration by increasing energy expenditure. Comparable effects were observed in leptin-deficient ob/ob mice, while central treatment had no effects in agouti yellow mice (A y /a), suggesting melanocortin but not leptin receptor activation as an essential prerequisite for adiponectin-induced weight loss (15). In another study, however, peripheral administration of full-length adiponectin in A y /a mice increased energy expenditure, while central application was again without effect (16). Increased energy expenditure in adiponectintreated mice therefore might in part be mediated via peripheral adiponectin receptors, including those located at the luminal surface of the blood-brain barrier (BBB).However, systemic adiponectin levels increase after weight reduction, while that physiological state is clearly associated with reduced energy expenditure (17-19). Thus, the energy expenditure-increasing effects of adiponectin seem unlikely to play a major physiological role. The picture becomes even more confusing since the latest results indicate that mice with increased circulating adiponectin levels due to e...

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

“…A recent paper has reported negative data regarding the presence and/or transport of adiponectin into CSF [22]. It is unclear why the authors were unable to detect adiponectin in CSF.…”

“…How, exactly, the adiponectin trimer crosses the BBB is currently unknown. Adipor1 and Adipor2 have been detected in the brain [21] and on BBB endothelial cells [22], suggesting that a regulated receptor-mediated transport system may be the favourable mechanism of entry. However, the identification and kinetic properties of adiponectin transporters remains to be determined.…”

“…In addition, adiponectin was shown to induce Fos protein immunostaining and increase hypothalamic corticotrophin-releasing hormone synthesis in the paraventricular nucleus, suggesting the activation of hypothalamic sympathetic circuits [20]. Further evidence suggesting a role for adiponectin in the CNS originates from several studies reporting the levels of adiponectin receptors 1 and 2 (ADIPOR1 and ADIPOR2) in the brain [21] and, more specifically, in mouse hypothalamus and on brain endothelial cells of the BBB [22]; the latter may potentially serve as a transport system for receptor-mediated transcytosis of adiponectin across the BBB. However, a more specific role for these receptors remains to be defined.…”

“…However, the question of whether adiponectin plays a role centrally under normal physiological conditions has yet to be resolved. One recent study failed to detect the presence of adiponectin in human CSF [22] and, with another, reported that exogenous adiponectin does not cross the BBB in mice [22,23], concluding that direct effects of adiponectin on CNS pathways may not be relevant.…”

Peripheral tissue–brain interactions in the regulation of food intake

“…Adiponectin receptors have also been detected in the hypothalamus (Qi et al 2004) and the placenta (Caminos et al 2005). Very interestingly, it has recently been reported that adiponectin does not cross the BBB but modifies cytokine expression in the brain endothelial cells, making unlikely a direct effect of adiponectin in the CNS (Spranger et al 2006). …”