Endocrine Abstracts

Thyroid hormones (TH), among their pleiotropic actions, play a central role in the regulation of metabolism and in cognitive functions. Indeed, hypothyroidism is associated with a decrease in energy expenditure and lipid metabolism, and an impairment of memory. Metabolic deregulations induced by a high fat diet (HFD) generate peripheral inflammation, which promotes the development of neuroinflammation in various brain regions. This inflammatory state can disrupt neuronal homeostasis, leading to the alteration of synaptic plasticity and to memory disorders. Furthermore, a link between hypothyroidism and the development of neuroinflammation has previously been shown, particularly in the hippocampus, a brain structure rich in TH receptors. Our objective was to evaluate whether metabolic deregulations induced by hypothyroidism favor the development of neuroinflammation and thereby promote memory deficits. We compared the response to induced hypothyroidism in two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by an obesity resistance due to its high metabolic flexibility phenotype and the C57BL/6J mice, prone to HFD-induced obesity. Adult mice were fed with a low-iodine diet supplemented with 6-n-propyl-2-thiouracyl (PTU) for 7 weeks to induce hypothyroidism. Our results show that hypothyroidism, characterized by a decrease in serum T4 levels, led to metabolic deregulations, as an alteration of lipid metabolism in the liver of both strains. However, the decrease in hepatic lipid synthesis was compensated in WSB/EiJ mice by a mobilization of lipid reserves from white adipose tissue, but not in the C57BL/6J mice. No peripheral inflammatory response to hypothyroidism was observed in both strains. In the hippocampus of C57BL/6J mice treated with PTU, the decrease in intracellular T3 availability was accompanied by an activation of glial cells, a hallmark of neuroinflammation, associated with an impairment of spatial memory. In contrast, no inflammatory response was observed in the hippocampus of WSB/EiJ mice, which appeared to maintain their thyroid status by locally increasing T3 availability via compensatory mechanisms. Our results shed the light on the fact that serum thyroid status does not always reflect central thyroid status. Moreover, they demonstrated that the described link between hypothyroidism and neuroinflammation does not seem to be the consequence of metabolic deregulations induced by hypothyroidism but rather of an unbalance in the central thyroid signaling. Thus, our results emphasize the importance of maintaining central thyroid homeostasis to protect against the development of neuroinflammation, and in extension, of neurodegenerative diseases, given that neuroinflammation favors cognitive and memory impairments.