Belgardt, Bengt-Frederik (2010) Obesity-linked dysfunction of hypothalamic and pituitary circuits in regulation of energy homeostasis. PhD thesis, Universität zu Köln.
Insulin and leptin action in the central nervous system (CNS) controls food intake, energy expenditure and glucose metabolism, partially by regulating the activity of hypothalamic proopiomelanocortin (POMC) neurons. Moreover, insulin- and leptinstimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in the control of energy homeostasis. To delinearize the importance of pathways downstream of PI3K specifically in POMC cell regulation, mice with selective inactivation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in POMC-expressing cells were generated. These mice initially display hyperphagia, increased body weight and impaired glucose metabolism caused by reduced hypothalamic POMC expression. In contrast, older mice exhibit normalized food intake and body weight as well as enhanced insulin and glucose sensitivity, due to a progressive loss of POMC-expressing corticotrophs in the pituitary and subsequent severe hypocortisolism. Expression of a dominant negative mutant of FOXO1 specifically in POMC cells is sufficient to prevent initial hyperphagia, transiently increased body weight and reduced hypothalamic POMC expression in these knockout mice, but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cell function and survival in control of energy homeostasis and stress response. To understand potential pathomechanisms involved in neuronal insulin and leptin resistance, the effect of obesity on hypothalamic expression of inflammatory mediators was examined. High-fat feeding was found to induce hypothalamic expression of several of cytokines , which was not readily reversible by switching to low-fat diet. Since cytokines and lipids are known to activate c-Jun N-terminal kinases (JNKs), mice with JNK1 deficiency in Nestin-expressing cells (which include neurons and pituitary stem cells) were generated. These mice demonstrated increased hypothalamic insulin sensitivity, as well as reduced activation of the somatotrophic axis and elevated activation of the thyrotrophic axis, resulting in improved improved glucose tolerance, elevated systemic insulin sensitivity, and were protected against obesity-induced hepatosteatosis and adipose tissue dysfunction. Taken together, obesity-induced JNK1 activation in the hypothalamus and pituitary is a crucial event in the induction of CNS insulin resistance and systemic glucose intolerance caused by obesity.
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