BACKGROUND: Obesity is a leading health burden of the 21st century. Alterations of the individual endocrine stress response and the monoamine system may pathophysiologically contribute to the obesity pandemic and its metabolic and mental complications.
OBJECTIVES: (i) to measure hypothalamic-pituitary-adrenal (HPA) axis responsiveness and its relation to serum concentrations of the arginine-vasopressin (AVP) surrogate copeptin in subjects with obesity (OB) compared to non-obesity controls (NOC), (ii) to test whether HPA axis responsiveness and copeptin are related to central noradrenaline (NA) transporter (NAT) availability, (iii) to assess brain serotonin transporter (SERT) binding potentials in OB compared to NOC.
METHODS: 40 subjects with obesity (BMI > 35kg/m2) were compared to 25 non-obesity controls, matched for age and sex. (i) All individuals underwent the combined dexamethasone/corticotropin releasing hormone (dex/CRH) test. Plasma ACTH and cortisol curve parameters were derived, and copeptin was assessed in the 1500h sample. (ii) Positron emission tomography (PET) was applied in 10 OB and 10 NOC using the NAT-selective radiotracer S,S-[11C]O-methylreboxetine (MRB) and associated to curve indicators derived from the dex/CRH test as well as to copeptin. (iii) PET using the SERT selective radiotracer [11C] DASB was performed in 30 OB and 15 NOC for intergroup comparison.
RESULTS: (i) OB subjects showed an increased HPA axis responsiveness as measured by cortisol concentrations after CRH stimulation. Correspondingly, the AVP surrogate copeptin was higher in OB along with being significantly associated to HPA axis reactivity. OB subjects had a higher adrenal sensitivity as measured by a lower ACTH/cortisol ratio. (ii) In NOC, the HPA response was related to NAT availability of the amygdala and the orbitofrontal cortex while in OB, this association was located in the hypothalamus. (iii) There were no differences in SERT availability between OB and NOC, but a higher inter-regional SERT connectivity was observed in OB.
CONCLUSION: This work supports the notion of an increased endocrine stress response in human obesity, pointing to interacting alterations of the HPA and neurohypophyseal axes. Normally, these stress axes seem to be linked to prefrontal-limbic NA signaling, whereas a loss of this association in favor of a hypothalamic-centered relation is observed in OB. The SERT network pattern is more closely inter-related in OB, albeit central SERT concentrations per se do not differ between OB and NOC.:ABBREVIATIONS 4
LIST OF FIGURES 5
I. BIBLIOGRAPHIC DESCRIPTION 6
II. INTRODUCTION 7
2.1 Obesity as a global health burden 7
2.2 Neurobiology of stress 8
2.3 Stress and obesity 8
2.4 Neuroendocrine correlates of the stress response – The hypothalamic pituitary-adrenaland neurohypophyseal axes 9
2.4.1 Anatomy of the hypothalamic-pituitary-adrenal and neurohypophyseal axes 10
2.4.2 The role of CRH, ACTH and cortisol in the context of metabolism and obesity 11
2.4.3 The role of AVP in the context of metabolism and obesity 12
2.4.4 Measuring HPA axis responsiveness by means of the combined dexamethasonecorticotropin-releasing hormone (dex/CRH) test 12
2.4.5 Measuring AVP secretion by its equally-released surrogate copeptin 14
2.5 The noradrenergic system in the context of obesity and stress axis modulation 14
2.5.1 NA and its influence on feeding behavior16
2.5.2 The association of the noradrenergic system with the HPA and neurohypophyseal axes
16
2.5.3 Monoamine transporters as regulators of neurotransmitter signaling 17
2.5.4 Noradrenaline transporter imaging 18
2.6 The serotonergic system in obesity 19
2.6.1 Role of serotonin in the context of feeding behavior and metabolism 20
2.6.3 5-HTT imaging 21
2.7 Objectives and hypotheses 22
2.8 Study design 23
III. RESULTS 24
3. 1 Post-dexamethasone serum copeptin corresponds to HPA axis responsiveness in human obesity 24
3. 2 Central noradrenaline transporter availability is linked with HPA axis responsiveness and copeptin in human obesity and non-obese controls 34
3. 3 Central serotonin transporter availability in highly obese individuals compared with nonobese controls: A [11C] DASB positron emission tomography study 46
IV. SUMMARY 56
4.1 Subjects with obesity show an enhanced HPA axis responsiveness which correlates to serum concentrations of the AVP surrogate copeptin and abdominal fat distribution 56
4.2 HPA axis responsiveness and copeptin concentrations are differentially related to central NAT availability in subjects with obesity compared to non-obesity controls 58
4.3 Central serotonin transporter availability does not significantly differ in subjects with obesity compared to their non-obesity counterparts 59
4.4 Future direction 61
V. References 62
VI. APPENDICES 79
6.1 Curriculum vitae 79
6.2 Publications 81
6.3 Scientific contribution of the doctoral candidate to the publications 82
6.4 Declaration of the independent writing of this thesis 83
6.5 Acknowledgements 84
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:35557 |
| Date | 01 October 2019 |
| Creators | Schinke, Christian |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/acceptedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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