Maternal thyroid hormone is required for parvalbumin neurone development in the anterior hypothalamic area.

Thyroid hormone (TH) is crucial for brain development and function. This becomes most evident in untreated congenital hypothyroidism, leading to irreversible mental retardation. Likewise, maternal hypothyroxinaemia, a lack of TH during pregnancy, is associated with neurological dysfunction in the offspring, such as autism and reduced intellectual capacity. In the brain, TH acts mainly through TH receptor α1 (TRα1). Consequently, mice heterozygous for a dominant-negative mutation in TRα1 display profound neuroanatomical abnormalities including deranged development of parvalbumin neurones. However, the exact timing and orchestration of TH signalling during parvalbumin neurone development remains elusive. In the present study, we dissect the development of parvalbumin neurones in the anterior hypothalamic area (AHA) in male mice using different mouse models with impaired pre- and postnatal TH signalling in combination with bromodeoxyuridine birth dating and immunohistochemistry. Our data reveal that hypothalamic parvalbumin neurones are born at embryonic day 12 and are first detected in the AHA at postnatal day 8, reaching their full population number at P13. Interestingly, they do not require TH postnatally because their development is not impaired in mice with impaired TH signalling after birth. By contrast, however, these neurones crucially depend on TH through TRα1 signalling in the second half of pregnancy, when the hormone is almost exclusively provided by the mother. For the first time, our findings directly link a maternal hormone to a neuroanatomical substrate in the foetal brain, and underline the importance of proper TH signalling during pregnancy for offspring mental health. Given the role of hypothalamic parvalbumin neurones in the central control of blood pressure, the present study advocates the inclusion of cardiovascular parameters in the current discussion on possible TH substitution in maternal hypothyroxinaemia.

Angiotensin II impairs glucose utilization in obese Zucker rats by increasing HPA activity via an adrenal-dependent mechanism.

Angiotensin II (AngII) increases the activity of the hypothalamus-pituitary-adrenal (HPA) axis. We have previously demonstrated in obese Zucker rats (OZR) that AngII-induced HPA hyperreactivity was associated with impaired glucose utilization. The aim of this study was to specify the potential role of the adrenals in regulating AngII-dependent glucose homeostasis in obesity. Adrenal-specific AngII effects were determined regarding 1) the HPA axis by ACTH tests after treating OZR with AngII (9 µg/h, s.c.) for 3 months and 2) glucose utilization by oral glucose tolerance tests (OGTT) in OZR that were adrenalectomized (adx) or sham operated and treated for 1 month with AngII (9 µg/h, s.c.). AngII increased the corticosterone response after ACTH infusions, clearly indicating the key role of the adrenals for mediating stress reactions. Baseline levels of glucose and corticosterone were not altered by AngII treatment or by adrenalectomy. In contrast, AngII similarly reduced baseline insulin in sham and adxOZR. During OGTT, AngII increased glucose and corticosterone responses in shamOZR, whereas insulin was slightly diminished. This reaction pattern was lost when obese Zucker rats were adrenalectomized. In summary, we verified our hypothesis that the adrenal glands play a key role in worsening glucose homeostasis in obesity in response to AngII, which further supports recent findings that improvement in glucose utilization after AT1 blockade is related to reduced activity of the HPA axis.