bioRxiv Science⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/2022.12.22.521639

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

Chamas, L.·Seugnet, I.·Tanve, O.·Enderlin, V.·Clerget-Froidevaux, M.-S.
View original source ↗Export metadata ↓

Abstract

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.

Explore related subjects

physiologyPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Chamas, L., Seugnet, I., Tanve, O., Enderlin, V., Clerget-Froidevaux, M.-S.. 2022-12-23. Down regulation of the liver lipid metabolism induced by hypothyroidism in mice: metabolic flexibility favors compensatory mechanisms in white adipose tissue. https://doi.org/10.1101/2022.12.22.521639

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Thoracoabdominal pressure transmission during prone and supine cardiopulmonary resuscitation in fresh-frozen human cadavers

Background: Prone cardiopulmonary resuscitation (CPR) may be necessary when turning a prone patient supine would delay chest compressions. Although prone compressions can generate arterial pressures comparable with or greater than supine CPR, the pathway of pressure transmission is uncertain. We examined synchronized intrathoracic, intra-abdominal, and central arterial pressures in both supine and prone positions. Methods: Two thawed fresh-frozen adult cadavers underwent three, 2-minute mechanical CPR trials per position in a counterbalanced crossover sequence. Solid-state catheters recorded pleural, peritoneal, and central arterial pressures simultaneously. Trial-level outcomes included peak pressure, mean pressure, pressure-time area, and the mean peritoneal-to-pleural pressure gradient. Exploratory fixed-effects models included position, cadaver, and their interaction. Results: Prone CPR increased peak intrathoracic pressure by 7.04 mmHg, peak intra-abdominal pressure by 21.69 mmHg, and peak arterial pressure by 15.40 mmHg. Mean intra-abdominal and arterial pressures increased by 16.22 and 9.90 mmHg, respectively. The mean peritoneal-to-pleural gradient reversed direction from -8.46 mmHg supine to 4.85 mmHg prone. Intrathoracic pressure-time area increased 3.4-fold, from 1.62 to 5.46 mmHg{middle dot}s, and arterial pressure-time area increased 2.2-fold, from 2.96 to 6.42 mmHg{middle dot}s. Conclusions: Compared to supine, prone mechanical CPR generated higher arterial pressures and reversed the pressure relationship across the thoracoabdominal boundary in both cadavers. Higher abdominal pressure coincided with a larger intrathoracic pressure-time area, a pattern compatible with reduced caudal pressure dissipation.

physiology↗
bioRxiv2026

Hypothalamic Farnesoid X Receptor deficiency alters energy balance by modulating hepatic glucose production and adipose tissue metabolism through central insulin signaling.

Objectives: The bile acid nuclear receptor Farnesoid X Receptor (FXR, NR1H4) is a major regulator of metabolism and energy homeostasis in peripheral organs. It modulates bile acid, glucose, and lipid metabolism, as well as fat mass and body weight. However, FXR is also expressed in the brain, particularly in the hypothalamus, a key center for the regulation of energy homeostasis. Although one study has demonstrated a role for brain FXR activation in energy balance, its specific hypothalamic role is still unknown. Here, we examined the role of FXR in the mediobasal hypothalamus in the regulation of energy balance. Methods: We used a genetic approach combined with metabolic phenotyping to determine the effect of FXR invalidation in the mediobasal hypothalamus on metabolic parameters involved in the central regulation of energy homeostasis. Results: Our results demonstrate that hypothalamic FXR deficiency induces a positive energy balance, resulting in a reduction in energy expenditure due to alterations in glucose metabolism accompanied by structural changes in white adipose tissues. Conclusion: This study uncovers a previously unrecognized role for hypothalamic FXR in the central homeostatic control of energy balance, providing new insights into its contribution to peripheral glucose metabolism and adipose tissue structural remodeling.

physiology↗
bioRxiv2026

Rad and Phospholamban are Key Drivers of the Ventricular Adrenergic Response and Stress-Induced Arrhythmia

The adrenergic response is a fundamental mechanism that regulates heart rate (chronotropy), cardiac contractility (inotropy) and relaxation (lusitropy). Adrenergic stress is also a recognized trigger of arrhythmia in disease. Yet, our understanding of the underlying molecular basis remains incomplete. Protein kinase A (PKA) and the calcium/calmodulin-dependent kinase II (CaMKII) phosphorylate multiple targets proposed to participate in the adrenergic response, including the GTP-binding protein Rad, phospholamban (PLB) and ryanodine receptor 2 (RyR2). Here we demonstrate that phosphorylation of both Rad and PLB is necessary for inotropy and lusitropy. We show that changes in cardiac contractility and relaxation are primarily dependent on intracellular calcium handling. Finally, we report that Rad and PLB control stress-induced arrhythmogenesis, despite the phosphorylation of other pro-arrhythmic targets. We have identified the essential molecular components of the adrenergic response, resolving a long-standing debate in cardiac excitation-contraction coupling and refining current models of sympathetic regulation in health and disease.

physiology↗