The paradoxical lean phenotype of hypothyroid mice is marked by increased adaptive thermogenesis in the skeletal muscle.

Obesity is a major health problem worldwide, given its growing incidence and its association with a variety of comorbidities. Weight gain results from an increase in energy intake without a concomitant increase in energy expenditure. To combat the obesity epidemic, many studies have focused on the pathways underlying satiety and hunger signaling, while other studies have concentrated on the mechanisms involved in energy expenditure, most notably adaptive thermogenesis. Hypothyroidism in humans is typically associated with a decreased basal metabolic rate, lower energy expenditure, and weight gain. However, hypothyroid mouse models have been reported to have a leaner phenotype than euthyroid controls. To elucidate the mechanism underlying this phenomenon, we used a drug-free mouse model of hypothyroidism: mice lacking the sodium/iodide symporter (NIS), the plasma membrane protein that mediates active iodide uptake in the thyroid. In addition to being leaner than euthyroid mice, owing in part to reduced food intake, these hypothyroid mice show signs of compensatory up-regulation of the skeletal-muscle adaptive thermogenic marker sarcolipin, with an associated increase in fatty acid oxidation (FAO). Neither catecholamines nor thyroid-stimulating hormone (TSH) are responsible for sarcolipin expression or FAO stimulation; rather, thyroid hormones are likely to negatively regulate both processes in skeletal muscle. Our findings indicate that hypothyroidism in mice results in a variety of metabolic changes, which collectively lead to a leaner phenotype. A deeper understanding of these changes may make it possible to develop new strategies against obesity.

Endoplasmic reticulum stress participates in the pathophysiology of mercury-caused acute kidney injury.

Acute exposure to mercury chloride (HgCl2) causes acute kidney injury (AKI). Some metals interfere with protein folding, leading to endoplasmic reticulum stress (ERS), and the activation of cell death mechanisms, but in the case of mercury, there is no knowledge about whether the ERS mediates tubular damage. This study aimed to determinate if HgCl2 causes an AKI course with temporary activation of ERS and if this mechanism is involved in kidney cell death. Male mice were intoxicated with 5 mg/kg HgCl2 and sacrificed after 24, 48, 72, and 96 h of mercury administration. The kidneys of euthanized mice were used to assess the renal function, oxidative stress, redox environment, antioxidant enzymatic system, cell death, and reticulum stress markers (PERK, ATF-6, and IRE1α pathways). The results indicate temporary-dependent renal dysfunction, oxidative stress, and an increase of glutathione-dependent enzymes involved in the bioaccumulation process of mercury, as well as the enhancement of caspase 3 activity along with IRE1a, GADD-153, and caspase 12 expressions. Mercury activates the PERK/eIF2α branch during the first 48 h. Meanwhile, the activation of PERK/ATF-4 branch allowed for ATF-4, ATF-6, and IRE1α pathways to enhance GADD-153. It led to the activation of caspases 12 and 3, which mediated the deaths of the tubular and glomerular cells. This study revealed temporary-dependent ERS present during AKI caused by HgCl2, as well as how it plays a pivotal role in kidney cell damage.

Maternal Thyroid Hormone Deficiency During Gestation and Lactation Alters Metabolic and Thyroid Programming of the Offspring in the Adult Stage.

Environmental stimuli during critical developmental stages establish long-term physiological and structural patterns that "program" health during adult life. Little is known about how alterations in hormonal supply might have consequences in metabolic and thyroid programming. This work aims to prove that alterations in the supply of thyroid hormones during gestation and lactation have long-term consequences in the metabolic and thyroid programming of the offspring. Female Wistar rats were divided into euthyroid, hypothyroid, and hypothyroid with 20 µg/day of s.c. thyroxine (T4), replacement wet nurses. Rats were mating, and after birth, pups were grouped according to their wet nurses group. Milk quality of wet nurses was assessed on days 7, 14, and 21. Body mass gain and energy intake of the offspring were monitored for 28 weeks after weaning. At sacrifice, we extracted and weighed their thyroid gland and adipose reserves, and collected blood to measure its metabolic and thyroid profiles. Hypothyroid wet nurses presented a persistent low quality of milk, while both male and female hypothyroid offspring presented lower body mass gain, higher blood glucose, dyslipidemia, hyperinsulinemia, and hyperleptinemia, as well as lower total adipose reserves, but higher visceral reserve, diminished T3 and T4 concentrations, and lower weight of thyroid gland. Thyroxine replacement prevented all changes in both wet nurses and pups. We conclude that maternal thyroid hormone deficiency during congenital and lactation stages alters the metabolic and thyroid programming of the offspring, while the reestablishment of maternal thyroid status during critical periods of development can prevent these alterations.

Hypothyroidism Causes Endoplasmic Reticulum Stress in Adult Rat Hippocampus: A Mechanism Associated with Hippocampal Damage.

Thyroid hormones (TH) are essential for hippocampal neuronal viability in adulthood, and their deficiency causes hypothyroidism, which is related to oxidative stress events and neuronal damage. Also, it has been hypothesized that hypothyroidism causes a glucose deprivation in the neuron. This study is aimed at evaluating the temporal participation of the endoplasmic reticulum stress (ERE) in hippocampal neurons of adult hypothyroid rats and its association with the oxidative stress events. Adult Wistar male rats were divided into euthyroid and hypothyroid groups. Thyroidectomy with parathyroid gland reimplementation caused hypothyroidism at three weeks postsurgery. Oxidative stress, redox environment, and antioxidant enzyme markers, as well as the expression of the ERE through the pathways of PERK, ATF6, and IRE1, were evaluated at the 3rd and 4th weeks postsurgery. We found a rise in ROS and nitrite production; also, catalase increased and glutathione peroxidase diminished their activities. These events promote an enhancement of the lipoperoxidation, as well as of γ-GT, myeloperoxidase, and caspase 3 activities. With respect to ERE, there were ATF6, IRE1, and GADD153 overexpressions with a reduction in mitochondrial activity and GSH2/GSSG ratio. We conclude that the endoplasmic reticulum stress might play a pivotal role in the activation of hypothyroidism-induced hippocampal cell death.