Casale, C; (2015) Investigation of Neuropeptide Y as a metabolic marker and its effects on adipose vasculature and brainstem astrocytes. Doctoral thesis , UCL (University College London).

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Abstract

Subsets of morbidly obese patients do not appear to exhibit the expected comorbidities, as well as the fact that heightened sympathetic nervous system (SNS) activity has been known to affect metabolism. In this study, Neuropeptide Y (NPY), an SNS co-transmitter is explored as a possible biomarker for unhealthy obesity. The aims of the study were to identify a normoinsulinemic/insulin sensitive morbidly obese Caucasian patient cohort, compare differences in NPY levels in the circulation and adipose tissue between the normoinsulinemic and hyperinsulinemic subjects. I explored the hypothesis that elevated circulating peripheral NPY causes metabolic abnormalities by mediating changes in the normal function of brain stem regulatory mechanisms via inflammation of astrocytes as shown in an in vitro model of primary cell line of human fetal brain stem astrocyte cell line. Blood and abdominal adipose tissue samples were obtained from consenting, morbidly obese patients awaiting bariatric surgery for recruitment in the study. Adipokines and NPY were measured as well as gene and protein expression by real-time PCR and histology. Effect of NPY was determined on a human brainstem astrocytic primary cell-line using immunohistochemistry, real time PCR, cytokine ELISA, intracellular secondary messengers via ELISA and fluorescence microscopy. Secreted lactate levels were measured by calorimetric assays. Differences were found between metabolically healthy obese (MHO) and pathologically obese (PO)/diabetic groups in certain adipokines and insulin sensitivity, which were maintained after surgical weight loss. Differences in adipocyte cell size were visible between the two groups both in subcutaneous and omental adipose tissue depots but inflammatory cell infiltration was not different. Brain stem astrocytes expressed NPY receptors and IL-6 secretion from the astrocytes increased when exposed to a combination of NPY and noradrenaline, reflected by changes in intracellular cAMP. Cytokine array showed increases in various inflammatory cytokines under the same treatment. IL-6 treatment increased astrocyte lactate levels. In astrocytes there was greater level of adrenergic signalling and secretion of IL-6 and lactate by the cells, which could mean different metabolic balance of astrocytes and long-term effects on astrocyte chemosensing function. These findings suggest differences in susceptibility to obesity associated pathologies linked to a synergistic modulation between the intracellular signalling pathways of astrocytes, being regulated at least partially by components of the CNS and having a direct effect on the cells. Perhaps these would pave the way for targeted treatment modalities. In vivo studies in an analogous animal model would further clarify the connection between elevated peripheral NPY and its central effects on the brainstem astrocytes in mediating metabolic disease.

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