Neuronal control of endocrin activity

Endocrine systems coordinate the functioning of different organs, energy balance and reproduction in cooperation with the central nervous system. Disruption of the coordination of these processes results in severe pathological conditions of the body involving several organ systems. Our institutional research strategy is to understand the central nervous system mechanisms that regulate energy balance, linking stress and metabolic regulation, and may provide the basis for the development of new personalised therapeutic strategies.
In Europe, obesity has reached epidemic levels, leading to serious and extremely costly health problems, reducing life expectancy, e.g. type 2 diabetes, cardiovascular disease. Despite these serious health and socioeconomic impacts, we do not have effective anti-obesity drug therapies. Therefore, the exploration of mechanisms regulating energy balance is of paramount importance, which may contribute to provide new anti-obesity drug targets for the pharmaceutical industry.
Similarly, the biological basis of reproductive decline, which is also to a large extent linked to endocrine disruption, is a major problem. Genetic disorders, metabolic disturbances, stress effects, the ageing process and artificial compounds that influence endocrine functions can disrupt the hypothalamic neuronal network responsible for reproduction, causing disturbances of central nervous system origin as well as infertility.
The institute's research strategy is to focus on the neuroscience of endocrine disruption, combining state-of-the-art genomics, metabolomics, transgenics and imaging techniques to elucidate the neuroscience processes that may lead to infertility and morbid obesity.

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Hypothalamic regulatory mechanisms of reproduction

Gonadotropin-releasing hormone (GnRH)-synthesizing neurons represent the final output pathway of the hypothalamus in the neuroendocrine control of reproduction. Pulsatile GnRH secretion into the hypophysial portal circulation regulates the synthesis and release of the two pituitary gonadotropins, LH and FSH, which in turn, govern gonadal functions. Gonadal sex steroid hormones exert positive and negative feedback effects on the neurosecretory output of GnRH neurons via mechanisms that are poorly understood. A major research focus of the Laboratory of Endocrine Neurobiology has been on the neuronal and hormonal mechanisms that regulate GnRH neuronal functions.

Regulation of cortical functions by estradiol

The sex hormone 17β-estradiol (E2) is primarily synthesized in maturing ovarian follicles. Cyclic changes in serum E2 levels across the menstrual cycle exert profound effects on reproductive tissues in women. E2 also plays an important role in the maintenance of normal limbic and cortical functions. Around menopause, when E2 levels decline the incidence of cognitive and mood disorders increases, which can be prevented with hormone replacement therapy. A major research interest of the Laboratory has been in the molecular mechanisms whereby E2 preserves good mood, capability of learning and processing memory via interactions with cortical and limbic structures. The classic actions of E2 are mediated by two estrogen receptor isoforms, ERα and ERβ. They are ligand-dependent transcription factors which regulate gene expression in the presence of E2. Prefrontal cortex (PFC) and the hippocampus are known targets of steroid hormone signaling.

Central regulatory mechanisms of metabolism

With support of the European Framework Programmes (5-7), we have been collaborating with outstanding European research laboratories of this scientific field  to elucidate novel neuronal and hormonal mechanisms that control metabolism centrally. These studies have explored several, new regulatory channels:

Mechanisms underlying tissue hypothyroidism in the brain during thyroxine substitution therapy

Our aim is to identify the basic cellular and molecular pathways that underlie the symptoms of hypothyroidism in a group of patients who respond poorly to thyroxine (T4) monotherapy. While the therapy is able to normalize the TSH of these patients, they still suffer from symptoms of tissue hypothyroidism that adversely affect cognitive function and regulation of energy homeostasis. 

Development of thyroid hormone gradients in the nervous system

It is known that thyroid hormone (TH) signalling is compartmentalized in the brain; glial cells are responsible for type 2 deiodinase (D2)-mediated TH activation, while neurons regulate their intracellular TH levels by type 3 deiodinase (D3) catalyzed inactivation. Little is known however on how TH are presented to neurons and how the active and inactive forms of TH are transported between cells and brain regions. 

Altered regulation of thyroid hormone economy under physiological and pathophysiological conditions

During development, the negative thyroid hormone (TH) feedback setting ("set-point") of the hypothalamo-pituitary-thyroid (HPT) axis is fixed for the entire life-span, but TH levels required for optimal tissue function vary in an age-dependent manner. However, the feedback regulation of the HPT axis is not able to adapt to this changing demand by changing the fixed set-point, that may contribute to age-dependent impairments of tissue function. Our aim is to investigate whether there are mechanisms that may contribute to age-dependent regulation of tissue-specific TH homeostasis despite the fixed set-point of the HPT axis.

Effect of endocrine disruptors on thyroid hormone homeostasis

Environmental pollution is rapidly increasing the amount of substances known as endocrine disruptors, that potentially exert a disruptive effects on hormone homeostasis, including thyroid hormone (TH) economy. These among others include plastic additives, pesticides, veterinary products, and their effects can vary widely. 

Central regulation of the hypothalamic-pituitary-thyroid (HPT) axis

The hypothalamic-pituitary-thyroid (HPT) axis primarily functions to maintain normal, circulating levels of thyroid hormones that are essential for the biologic function of all tissues including brain development, regulation of cardiovascular, bone and liver function, food intake and energy expenditure among many others.

Regulation of energy homeostasis by GLP-1 receptive neuronal networks

Glucagon-like peptide-1 (GLP-1) is an incretin hormone. It is derived from the posttranslational processing of proglucagon. This prohormone is synthesized by three cell populations, the neuroendocrine L cells of the intestinal mucosa, the ß cells of the pancreatic Langerhans islands and in a neuronal population located in the nucleus tractus solitarii (NTS) and intermediate reticular nucleus of the medulla oblongata.

Tissue specific regulation of thyroid hormone action

While the HPT axis warrants the stability of circulating thyroid hormone levels, a complex machinery of thyroid hormone transporters, metabolizing enzymes, receptors and co-regulators ensures that the local thyroid hormone action meets the highly variable requirements of the different tissues.