Energy homeostasis : crosstalk between adipose tissue and the human hypothalamus

There is a worldwide epidemic of obesity. Weight rise is a consequence of continuous positive energy balance which leads to accumulation of body fat. Recent insights into adipose tissue (AT) biology have led to the conclusion that the adipocyte is not just a storage depot for triglycerides but also an endocrine organ. AT secretes proteins, such as leptin, which control central appetite regulation in the human hypothalamus. In contrast, several other proteins and neurotransmitters regulate central energy balance, but can also influence AT metabolism to elicit feedback on fat accumulation. This suggests a close link between AT and the brain within an AT-to-brain crosstalk system including feedback circuits. This thesis examines firstly, the potential of crosstalk between AT and the brain by other adipokines and secondly, the brain-AT crosstalk by expression of neurotransmitters and their receptors in AT. The study establishes the presence of the adipokines adiponectin and resistin in human cerebrospinal fluid and immunohistochemistry showed adiponectin receptors in energy regulating nuclei of the hypothalamus. Furthermore, this thesis established that the orexigenic neurotransmitters NPY and ghrelin are secreted by human adipocytes, where they enhance lipid accumulation. Further, that NPY levels increase with obesity and its in vitro secretion is enhanced by insulin. This may play an important role in the pathogenesis of the metabolic syndrome and may induce an escape of the appetite behaviour towards positive energy balance. Finally, this thesis highlights the influence of a depot-specific innervation of AT on energy homeostasis by establishing presence of nicotinic receptors in human adipocytes, which may play a role in smoking induced changes in adipokine secretion and fat mass. In conclusion, this thesis suggests a tight interplay between AT and the brain and highlights its potential relevance in human pathophysiology