High Expression of Thyroid Hormone Receptors and Mitochondrial Glycerol-3-phosphate Dehydrogenase in the Liver Is Linked to Enhanced Fatty Acid Oxidation in Lou/C, a Rat Strain Resistant to Obesity

Abstract

Besides its well recognized role in lipid and carbohydrate metabolisms, glycerol is involved in the regulation of cellular energy homeostasis via glycerol-3-phosphate, a key metabolite in the translocation of reducing power across the mitochondrial inner membrane with mitochondrial glycerol-3-phosphate dehydrogenase. Here, we report a high rate of gluconeogenesis from glycerol and fatty acid oxidation in hepatocytes from Lou/C, a peculiar rat strain derived from Wistar, which is resistant to age-and diet-related obesity. This feature, associated with elevated cellular respiration and cytosolic ATP/ADP and NAD ؉ /NADH ratios, was linked to a high expression and activity of mitochondrial glycerol-3-phosphate dehydrogenase. Interestingly, this strain exhibited high expression and protein content of thyroid hormone receptor, whereas circulating thyroid hormone levels were slightly decreased and hepatic thyroid hormone carrier MCT-8 mRNA levels were not modified. We propose that an enhanced liver thyroid hormone receptor in Lou/C may explain its unique resistance to obesity by increasing fatty acid oxidation and lowering liver oxidative phosphorylation stoichiometry at the translocation of reducing power into mitochondria.

Increased Abdominal Adiposity Exacerbates Ex-Vivo Cardiac Reperfusion Injury through Augmented Mitochondrial Oxidative Stress

“…It is thought to be caused by a decreased mitochondrial ATP:O ratio, possibly related to increased uncoupling of protein-3 expression [50]. It validates the hypothesis previously assumed [20] and suggests that the Lou/C rat displayed a higher metabolic efficiency. Moreover, we have shown, for the first time that Wistar rats displayed higher cardiac lactate production and a higher ratio between the amount of lactate released and oxygen consumed when compared to Lou/C rats.…”

“…The Lou/C rat, an animal selected from the Wistar strain, displays spontaneous caloric restriction [16,17], which appears to be related to reduced expression of orexigenic neuropeptides [18]. This rat phenotype can maintain insulin sensitivity throughout its lifespan [19], and displays a resistance to age-and diet-induced obesity compared to Wistar rats [20,21]. The Lou/C rat has lower plasma leptin and higher adiponectin concentrations [22,23], reflecting lower visceral fat deposition [19,21,[24][25][26].…”

Effects of a high-fat diet on energy metabolism and ROS production in rat liver

“…It is known that octanoate addition markedly inhibits gluconeogenesis from glycerol (compare Fig. 3A) because of the reduced cytosolic state, which controls this pathway [15,32]. Interestingly, the HF diet has a divergent effect on gluconeogenesis depending on the presence of octanoate.…”

“…3A, gluconeogenesis change was biphasic: it first increased and declined thereafter, despite further increases in infused substrate concentrations. The flux inhibition at high glycerol concentration was expected to be due to the inhibitory effect of glycerol-3-phosphate accumulation on glucose-6-phosphatase [29,32]. It is known that octanoate addition markedly inhibits gluconeogenesis from glycerol (compare Fig.…”

Oxidative Stress and Antioxidant Status in Hypo- and Hyperthyroidism

“…Triiodothyronine (T3) and thyroxin (T4) circulating hormones are involved in the modulation of the physiological mitochondrial respiration process [105]. These agents were reported to change the number and activity of the mitochondrial respiratory chain components.…”