Nilsson 2010 Thesis

Nilsson I (2010) Hypothalmic regulation of food intake – focus on the anx/anx mouse. Thesis Karolinska Institute Stockholm, Department of Molecular Medicine and Sugery, 62pp.

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Nilsson I (2010) Thesis

Abstract: See Free Text • Keywords: hypothalmus; food intake; reactive oxygen species; complex I

• O2k-Network Lab: SE Stockholm Morein T

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Abstract: The main goal of this thesis is to increase the knowledge about one of the most important tasks of the brain, the hypothalamic regulation of food intake. The hypothalamus is considered to be the brain’s main center for regulation of food intake and it is integrating signals regarding energy status, from the body, to initiate a proper behavioral response. A malfunctioning of this sensitive system can cause disturbed eating behavior, and have serious consequences for the organism’s well being. Disturbed eating behavior is not only part of the traditional eating disorders, such as anorexia nervosa and bulimia nervosa, but also contributes to overweight and obesity, thereby increasing the risk for several severe disorders and conditions. In addition, anorexia/cachexia is a frequent complication of failure to thrive in infants, malignant tumors and inflammatory diseases, and is contributing significantly to the mortality of these disorders. We use the unique anorectic anx/anx mouse as a model system for regulation of food intake. In Paper I, we studied the normal development of the projections from NPY/AGRP expressing neurons in the arcuate nucleus (Arc), in normal mouse, and were able to conclude that the first three postnatal weeks appear to be critical for the development of this hypothalamic food intake‐regulating system. Previous studies have shown several neurochemical abberances in the hypothalamus of the anx/anx mouse, in particular in the distribution of neurotransmitters and ‐peptides known to have a potent regulatory role in the control of food intake, such as NPY, AGRP, CART and POMC. In order to evaluate when these aberrances first appear, we compared the development of the NPY/AGRP system in anx/anx with +/+ mice in Paper II. We concluded that the NPY/AGRP system in anx/anx mice develop as in +/+ mice until P12, after which it appears as if the normal gradual increase in fibers cease and even decrease. In addition, we detected a region specific activation of microglia in several hypothalamic, as well as extra hypothalamic areas, in anx/anx mice from P12 and onwards. Interestingly, these were all areas in which we previously detected a reduced density of NPY/AGRP‐ir fibers in anx/anx mice, indicating that the aberrant hypothalamic neurochemistry in the anx/anx mice could be related to an inflammatory/neurodegenerative process. To further investigate this possibility we analyzed the expression of MCH class I. In Paper III we show expression of MHC class I mRNA and protein in the projection areas of the Arc neurons, to a large extent attributed to microglia, but remarkably also in a few arcuate‐neuron , in the anx/anx mice,. We also found evidence for hypothalamic degeneration in the anx/anx mouse, by showing co‐labeling of NPY and active caspase 6 in Arc, DMH, amygdala and zona incerta. Caspase 6 is required for axonal degeneration, and has been implicated in the pathology of neurodegenerative disorders. Taken together, this provides evidence of a neurodegenerative process in hypothalamus of the anx/anx mice. In Paper IV, we aimed to identify the anx gene and mutation, as well as the underlying mechanism causing the anorectic phenotype of the anx/anx mouse. We concluded that the anorexia and premature death of the anx/anx mouse is realated to hypothalamic mitochondrial dysfunction and that the anx mutation leads to lower levels of the Ndufaf1 gene and protein. This leads to less fully assembled complex I in the mitochondrial oxidative phosphorylation system, as well as accumulation of sub‐complexes resulting and increased production of reactive oxygen species. The increased levels of reactive oxygen species can initially act as a signaling molecule affecting hypothalamic neurons, leading to reduced food intake, oxidative stress and in the long run to inactivation and degeneration of Arc food intake‐regulating neurons in anx/anx mice.