Universität zu Köln

Paeger, Lars (2013). The Role of Noradrenaline in Energy Homeostasis. PhD thesis, Universität zu Köln.

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Abstract

Obesity is a condition that is associated with excessive weight gain and fat mass storage whose prevalence is increasing within western populations. A variety of co-morbidities are linked to obesity such as type 2 diabetes mellitus, cardiovascular diseases and neurodegenerative disorders, including Alzheimer’s disease and Parkinson’s disease. Together, this contributes to substantial costs of healthcare programs. In non-obese indi- viduals, energy intake and energy expenditure is precisely matched over a long time period in order to maintain energy resources and fat mass. This mechanism, termed energy homeostasis is accomplished by regulatory neuronal networks in the central nervous system (CNS). To better understand and counteract obesity and its co-morbidities, increasing efforts are being made to define the control mechanisms in the CNS, that regulate body weight and energy homeostasis. The focus of this study is the noradrenergic (noradrenaline; NA) modulation of energy homeostasis. Anti-obesity drugs, for example amphetamines, can exert strong anorexigenic effects on eating behaviour in humans. However, these drugs generally affect multiple transmitter and neuromodulator pathways, such as the dopaminergic and serotonergic system, leading to undesired side effects. Pharmacological studies indicate that the anorexigenic effect of amphetamine and related drugs are caused in part by modulation of the NA system. In order to devise strategies and develop specific drugs with minimized side effects in support of weight loss programs, it is critical to understand in detail the mechanisms in the CNS by which NA contributes to energy homeostasis. Besides the well established role of the paraventricular nucleus of the hypothalamus in NA-mediated modulation of food intake, studies indicate that NA input on the homeostatic system in the arcuate nucleus of the hypothalamus (ARC) might also modulate eating behaviour. In the ARC, two key neuronal populations, pro-opiomelanocortin (POMC) and agouti-related peptide (AgRP) expressing neurons sense and integrate peripheral and nutritional signals. Once activated, POMC neurons promote satiety and xi activation of AgRP neurons leads to food intake and decreased energy expenditure. Mechanisms that mediate the possible NA action in the ARC are unknown. In this study, the effect of NA on POMC and AgRP expressing neurons has been investigated. Application of NA inhibits POMC neurons, while AgRP neurons are excited. Pharmacological experiments revealed that these effects are mediated by α2A- and α1A-adrenergic receptors (AR). This suggests a potent NA modulation of food intake. With respect to these effects, afferent projections from NA nuclei and the conditions under which NA is released into the ARC are of greatest interest. As a potential NA source, the locus coeruleus (LC) in the brainstem contains 50% of the NA neurons in CNS. Efferent projections from the LC to the ARC have been identified. Besides the contribution to autonomic functions in general, studies indicate that the LC is also involved in glucose metabolism and the control of brown adipose tissue (BAT). Moreover, BAT thermogenesis is dependent on NA and plasma glucose. Therefore, the effects of changes in extracellular glucose concentrations have been inves- tigated. Around 40% of neurons in the LC responded with increasing spike frequency due to elevated glucose levels, identifying these neurons as glucose-excited. A small subpopulation responded with a moderate inhibition and is considered as glucose- inhibited. Expression of a mutant variant of the ATP dependent potassium channel in mice silenced a large number of LC neurons and abolished responses to glucose. Moreover, sympathetic nerve activity was reduced and led to a white-adipose-tissue-like morphology of BAT, alongside with impairment of thermogenesis. As a consequence of decreased energy expenditure, these mice developed obesity. The modulation of POMC and AgRP neurons by NA indicates a critical role of the catecholamine in the control of energy homeostasis. Moreover, this study reveals that the LC contains glucose-sensing neurons and contributes to the control of glucose metabolism and the activity of BAT. Its projection patterns in the CNS identify the LC as a potential source for NA release into the ARC. These results lead to new insights and the expansion of the current role of NA in the control of energy homeostasis. Importantly, this may help to develop new strategies and drugs with minimized side effects in the treatment of obesity.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Paeger, Lars lars.paeger@uni-koeln.de UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-55899
Date:	26 August 2013
Language:	English
Faculty:	Faculty of Mathematics and Natural Sciences
Divisions:	Faculty of Mathematics and Natural Sciences > Department of Biology > Zoologisches Institut
Subjects:	Natural sciences and mathematics Life sciences
Uncontrolled Keywords:	Keywords Language Noradrenaline, Obesity, Energy Homeostasis English
Date of oral exam:	15 October 2013
Referee:	Name Academic Title Kloppenburg, Peter Prof. Dr.
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/5589