Adipocyte-Brain-Crosstalk
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1
University of Luebeck, Medical Clinic 1, Germany
The initial discovery of leptin, an appetite-suppressing hormone originating from fat tissue, substantially supported the idea that fat-borne factors act on the brain to regulate food intake and energy expenditure. Since then, a growing number of cytokines has been found to be released from adipose tissue thus acting in an endocrine manner. These adipocytokines include e.g. adiponectin, apelin, resistin and visfatin, but also inflammatory cytokines and steroid hormones such as estrogens and glucocorticoids. They are secreted from their adipose depots and differ in terms of release stimuli, downstream signalling and their action on the brain. Clearly, adipocytokines play a prominent role in the central control of body weight and the deregulation of this circuit may lead to the development of obesity and related disorders.
Among these adipocytokines leptin has been studied most extensively. To access the brain, leptin is transported across the blood brain barrier via a saturable mechanism. Within the CNS, under physiological conditions it acts to reduce food intake and to increase energy expenditure. This is mediated, at least in part, by hypothalamic mechanisms (arcuate nucleus) leading to stimulation of sympathetic nerve activity. The importance of such a feedback control by an adipocyte-brain-crosstalk is underlined by the massive obesity in rodents harboring a defect leptin gene product or leptin receptors and in humans with functional mutations of the leptin gene. Most experimental and human forms of obesity are associated with a lessened sensivity to leptin’s action, commonly referred to as leptin resistance - resulting from alterations in hypothalamic neuronal signalling and/or transport across the blood brain barrier. The latter e.g. can be circumvented by e.g. intranasal application of leptin. We have shown, that via this route leptin reaches the hypothalamus in supraphysiological amounts and acts to reduce food intake and body weight gain in experimental animals.
These discoveries initiated an increased exploration into the crosstalk between adipocytokines and the brain. The adipocytokine adiponectin, thought to be protective by enhancing insulin sensivity is one of the most abundantly secreted proteins by white adipose tissue. In contrast to leptin, adiponectin is decreased in obesity, inversely related to glucose insulin and increases during fasting. Current consensus is that the high molecular weight form is transported across the blood brain barrier and most relevant to the centrally mediated weight reducing effect of this adipocytokine. Still, there are conflicting data on the brain actions of adiponectin and the molecular mechanisms clearly have to be elucidated.
Nesfatin (NEFA/nucleobindin 2 encoded satiety-and-fat-influencing protein) is an adipocytokine both expressed in the CNS and white adipose tissue. In the CNS, it is present in the hypothalamus and dose-dependently reduces food intake in rats. When investigating fragments of nesfatin it was shown that nesfatin-1 exerts a dose dependent anorexigenic effect. Interestingly, it can cross the blood-brain barrier via a non saturable transmembrane diffusion, consistent with its low lipophilicity. This clearly raises the possibility, that peripheral nesfatin-1 may access the central nervous system. Most interesting, as with leptin, intranasal application of nesfatin-1 reduces food intake in rats.
We also recently demonstrated that visfatin concentrations in human CSF decrease with rising body fat and that insufficient availability of visfatin or its resistance in the brain may be linked to the pathogenesis of obesity.
In our presentation we will thus focus on cross-talk mechanisms and the deregulation of adipocytokines at the expression level and/or sites of central action which eventually will lead to the development and perpetuation of obesity and diabetes.
Conference:
2nd Selfish Brain Conference
New research on the neurobiology of ingestive behaviour, 23554 Luebeck, Germany, 27 May - 28 May, 2010.
Presentation Type:
Oral Presentation
Topic:
Talks
Citation:
Lehnert
H
(2010). Adipocyte-Brain-Crosstalk.
Front. Neurosci.
Conference Abstract:
2nd Selfish Brain Conference
New research on the neurobiology of ingestive behaviour.
doi: 10.3389/conf.fnins.2010.08.00007
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Received:
12 Apr 2010;
Published Online:
12 Apr 2010.
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Correspondence:
Hendrik Lehnert, University of Luebeck, Medical Clinic 1, Luebeck, Germany, hendrik.lehnert@uk-sh.de