Inhibition of Thyroid Hormone Signaling in the Zona Incerta Alters Basal Metabolic Rate, Behavior, and Serum Glucocorticoids in Male Mice.

Background: It has long been known that thyroid disease can lead to changes in energy metabolism, thermoregulation, and anxiety behavior. While these actions have been partially attributed to thyroid hormone (TH) receptor α1 (TRα1) action in the brain, the precise neuroanatomical substrates have remain elusive. Methods: We used PET-CT scans to identify brain regions affected by TH. We then inhibited TRα1 signaling specifically in the most affected region, the zona incerta (ZI), a still mysterious region previously implicated in thermogenesis and anxiety. To this end, we used an adeno-associated virus (AAV) expressing a dominant-negative TRα1R384C in wild-type mice and phenotyped the animals. Finally, we used tyrosine hydroxylase-Cre mice to test specifically the contribution of ZI dopaminergic neurons. Results: Our data showed that AAV-mediated inhibition of TRα1 signaling in the ZI lead to increased energy expenditure at thermoneutrality, while body temperature regulation remained unaffected. Moreover, circulating glucocorticoid levels were increased, and a mild habituation problem was observed in the open field test. No effects were observed when TRα1 signaling was selectively inhibited in dopaminergic neurons. Conclusions: Our findings suggest that altered TH signaling in the ZI is not involved in body temperature regulation but can affect basal metabolism and modulates stress responses.

Differential Cellular Balance of Olfactory and Vomeronasal Epithelia in a Transgenic BACHD Rat Model of Huntington's Disease.

Background. For neurodegenerative diseases such as Huntington's disease (HD), early diagnosis is essential to treat patients and delay symptoms. Impaired olfaction, as observed as an early symptom in Parkinson´s disease, may also constitute a key symptom in HD. However, there are few reports on olfactory deficits in HD. Therefore, we aimed to investigate, in a transgenic rat model of HD: (1) whether general olfactory impairment exists and (2) whether there are disease-specific dynamics of olfactory dysfunction when the vomeronasal (VNE) and main olfactory epithelium (MOE) are compared. Methods. We used male rats of transgenic line 22 (TG22) of the bacterial artificial chromosome Huntington disease model (BACHD), aged 3 days or 6 months. Cell proliferation, apoptosis and macrophage activity were examined with immunohistochemistry in the VNE and MOE. Results. No differences were observed in cellular parameters in the VNE between the groups. However, the MOE of the 6-month-old HD animals showed a significantly increased number of mature olfactory receptor neurons. Other cellular parameters were not affected. Conclusions. The results obtained in the TG22 line suggest a relative stability in the VNE, whereas the MOE seems at least temporarily affected.

Dietary-Induced Low-Grade Inflammation in the Liver.

The literature describes a close correlation between metabolic disorders and abnormal immune responses, like low-grade inflammation (LGI), which may be one mechanistic link between obesity and various comorbidities, including non-alcoholic fatty liver disease (NAFLD). In our study, we investigated the influence of dietary composition on obesity-derived LGI in the liver. We used a dietary induced obesity mouse model of C57BL/6J mice fed with high fat diet (HFD, 60% fat, 20% protein, 20% carbohydrates) and two different controls. One was rich in carbohydrates (10% fat, 20% protein, 70% carbohydrates), further referred to as the control diet (CD), and the other one is referred to as the standard diet (SD), with a more balanced macronutrient content (9% fat, 33% protein, 58% carbohydrates). Our results showed a significant increased NAFLD activity score in HFD compared to both controls, but livers of the CD group also differed in their macroscopic appearance from healthy livers. Hepatic fat content showed significantly elevated cholesterol concentrations in the CD group. Histologic analysis of the cellular immune response in the liver showed no difference between HFD and CD and expression analysis of immunologic mediators like interleukin (IL)-1ß, IL-6, IL-10 and tumor necrosis factor alpha also point towards a pro-inflammatory response to CD, comparable to LGI in HFD. Therefore, when studying diet-induced obesity with a focus on inflammatory processes, we encourage researchers to carefully select controls and not use a control diet disproportionally rich in carbohydrates.