Hypothalamic cellular changes in neuroendocrine disorders. Human postmortem studies

Onderzoeksoutput: PhD Thesis (Proefschrift)PhD thesis (Proefschrift)

Samenvatting

The hypothalamus is one of the key brain regions involved in energy homeostasis, circadian rhythm, and behavioral outputs coordination. Solid evidence from murine models show that development and progression of metabolic disorders are rooted in neuronal and glial dysfunctions in the hypothalamus. While spatial and temporal changes in neurons and non-neuronal cells are well understood in animal models, little is known how translational those findings are in human with metabolic disorders. We profiled cellular and molecular changes in the hypothalamus of type 2 diabetes mellitus (T2DM) and Prader-Willi Syndrome (PWS) individuals. In the first section of this thesis, we evaluated the molecular and cellular signatures of hypothalamic dysfunction in PWS using state-of-art molecular techniques and histopathological profiling of human hypothalamic postmortem tissue. We dissected the neuroanatomic basis of circadian misalignments experienced by PWS individuals. Moreover, we characterized a pronounced glial dysfunction in hypothalamic area that controls energy metabolism and behavioral outputs; and different PWS subgenotypes present specific glial signatures leading to potential personalized medicine strategies in a genotype-dependent manner. Next, we explored the neuronal and glial hypothalamic profiles of T2DM individuals, especially focused on the hypothalamic paraventricular nucleus. Our data show that T2DM pathophysiology is connected to loss of oxytocinergic neurons, parallel to defective gliovascular coupling, and altered tanycytic lipid metabolism. In summary, we provide the cellular basis for hypothalamic dysfunction in different neuroendocrine disorders in humans.
Originele taal-2Engels
Begeleider(s)/adviseur
  • Fliers, E., Promotor, Externe Persoon
  • Swaab, D.F., Promotor
  • Yi, C.X., Co-promotor, Externe Persoon
  • Kalsbeek, A., Co-promotor
Datum van toekenning04 mrt. 2024
StatusGepubliceerd - 2024

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