Biology subjects

Chamas, L.

Publications and source records attributed to Chamas, L..

3 recordsLinked to original sources

bioRxiv2022

Down regulation of the liver lipid metabolism induced by hypothyroidism in mice: metabolic flexibility favors compensatory mechanisms in white adipose tissue

In mammals, the maintenance of energy homeostasis relies on complex mechanisms requiring tight synchronization between peripheral organs and the brain. Thyroid hormones (TH), among their pleiotropic actions, play a central role in these regulations. Hypothyroidism, which is characterized by low circulating TH levels, slows down the metabolism, leading to a reduction in energy expenditure, as well as in lipid and glucose metabolism, and to insulin resistance. Our objective was to evaluate whether metabolic deregulations induced by hypothyroidism could be avoid by regulatory mechanisms involved in metabolic flexibility. To this aim, we compared the response to hypothyroidism in two mouse strains, the wild-derived WSB/EiJ mouse strain characterized by a diet-induced obesity (DIO) resistance due to its high metabolic flexibility phenotype and the C57BL/6J mice, prone to DIO. 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 or hypothalamic inflammatory response to hypothyroidism was observed in both strains. Moreover, gene expression analysis showed that hypothyroidism stimulates the hypothalamic orexigenic circuit in both strains, but unchanged Mc4r and LepR expression in hypothyroid WSB/EiJ mice strain, which reflect their adaptability to maintain their body weight, contrary to C57BL/6J mice. Our results show that WSB/EiJ mice displayed a phenotype of resistance to metabolic dysregulations induced by hypothyroidism, by compensatory mechanisms. This response as well as their resistance to HFD-induced obesity highlights their adaptive capacities to maintain metabolic homeostasis, namely, their high metabolic flexibility, despite serum hypothyroidism. This model sheds light on the importance of local thyroid homeostasis to maintain lipid metabolism and metabolic homeostasis.

physiology↗

bioRxiv2022

Hippocampal hypothyroidism in mice promotes glial cell activation and spatial memory deficits.

Adult-onset hypothyroidism is associated with learning and cognitive dysfunctions, which may be related to alterations in synaptic plasticity. Local reduced levels of thyroid hormones (THs) may impair glia morphology and activity, and promote the increase of pro-inflammatory cytokine levels mainly in the hippocampus. Given that neuroinflammation induces memory impairments, hypothyroidism-related glia dysfunction may participate in brain disorders. Thus, we investigated the mechanisms linking hypothyroidism, neuroinflammation and spatial memory, from a protective prospective. We induced hypothyroidism in adult C57BL/6J and wild-derived WSB/EiJ male mice by a seven-week propylthiouracil (PTU) treatment. We previously showed that WSB/EiJ mice were resistant to high-fat diet (HFD)-induced obesity, showing no neuroinflammatory response through adaptive abilities, unlike C57BL/6J. As PTU and HFD treatments are known to induce comparable inflammatory responses, we hypothesized WSB/EiJ mice might also be protected against hypothyroidism-induced neuroinflammation. We showed that hypothyroid WSB/EiJ mice depicted no hippocampal neuroinflammatory response and were able to maintain their hippocampal thyroid signalling despite low circulating TH levels. In contrast, C57BL/6J mice exhibited disturbed hippocampal TH signalling, accompanied by neuroinflammation and memory impairment. Our results reinforce the preponderance of local TH levels over circulating levels and the major role of hippocampal glia reactivity in the establishment of memory deficits.

neuroscience↗

bioRxiv2018

Reduced central and peripheral inflammatory responses and increased mitochondrial activity contribute to diet-induced obesity resistance in WSB/EiJ mice.

ObjectivesEnergy balance disruption due to excess of calorie-rich food is considered to be one of the major players in the current worldwide obesity pandemic. In rodents, a high fat diet (HFD) induces not only obesity, but also inflammation and mitochondrial dysfunctions. To identify factors underlying diet-induced obesity (DIO) resistance we compared the wild-derived mouse strain WSB/EiJ, characterized by a striking resistance to DIO, with the more DIO-sensitive C57BL/6J strain.\n\nMethodsWe analysed circulating levels of lipids, cytokines and adipokines as well as hypothalamic markers of inflammatory status and mitochondrial activity in both strains exposed to HFD for three days (3d) or eight weeks (8wk). To identify hypothalamic genes potentially involved in these differential regulations, we selected 86 genes related to inflammation and mitochondrial pathways. We analysed their expression levels by high throughput microfluidic qPCR on RNA extracted from laser micro-dissected arcuate (ARC) and paraventricular (PVN) hypothalamic nuclei of the two strains of mice, under the different HFD treatments.\n\nResultsAfter 3d and 8wk HFD, C57BL/6J mice, in contrast to WSB/EiJ, displayed significantly increased body weight gain, and also increased circulating levels of leptin, cholesterol, HDL and LDL. WSB/EiJ mice displayed a lower inflammatory status, both peripherally (lower levels of circulating cytokines) and centrally (less activated microglia in the hypothalamus) as well as more reactive mitochondria in the hypothalamus. Principal Component Analysis and gene ontology analysis of gene expression data showed, first, that datasets segregated as a function of strain and second, allowed to identify the metabolic pathways involved. These results were reinforced by the identification of strain-specific differential expression of several individual hypothalamic genes as well as differential effects of HFD between strains.\n\nConclusionsAdaptation to metabolic stress in the DIO-resistant WSB/EiJ strain implicates enhanced lipid metabolism, lower peripheral and hypothalamic inflammatory status and higher mitochondrial activity than in the C57BL/6J strain. These results point to the implication of the hypothalamic inflammatory and mitochondrial pathways as key factors in the control of energy homeostasis and the resistance to DIO.\n\nDeclarations of interest: none\n\nHighlightsO_LIDiet-induced-obesity resistance of WSB/EiJ implicates enhanced lipid metabolism\nC_LIO_LIWSB/EiJ mice are protected from HFD-induced peripheral and central inflammation\nC_LIO_LIEnhanced hypothalamic transport and signalling of endocrine molecules in WSB/EiJ\nC_LIO_LIWSB/EiJ hypothalamic mitochondria dynamics differ from C57BL/6J\nC_LIO_LIDifferential regulation of hypothalamic inflammatory/mitochondria genes in WSB/EiJ\nC_LI

physiology↗