3,5-Diiodo-L-thyronine activates brown adipose tissue thermogenesis in hypothyroid rats

3,5-Diiodo-l-thyronine (T2), a thyroid hormone derivative, is capable of increasing energy expenditure, as well as preventing high fat diet-induced overweight and related metabolic dysfunction. Most studies to date on T2 have been carried out on liver and skeletal muscle. Considering the role of brown adipose tissue (BAT) in energy and metabolic homeostasis, we explored whether T2 could activate BAT thermogenesis. Using euthyroid, hypothyroid, and T2-treated hypothyroid rats (all maintained at thermoneutrality) in morphological and functional studies, we found that hypothyroidism suppresses the maximal oxidative capacity of BAT and thermogenesis, as revealed by reduced mitochondrial content and respiration, enlarged cells and lipid droplets, and increased number of unilocular cells within the tissue. In vivo administration of T2 to hypothyroid rats activated BAT thermogenesis and increased the sympathetic innervation and vascularization of tissue. Likewise, T2 increased BAT oxidative capacity in vitro when added to BAT homogenates from hypothyroid rats. In vivo administration of T2 to hypothyroid rats enhanced mitochondrial respiration. Moreover, UCP1 seems to be a molecular determinant underlying the effect of T2 on mitochondrial thermogenesis. In fact, inhibition of mitochondrial respiration by GDP and its reactivation by fatty acids were greater in mitochondria from T2-treated hypothyroid rats than untreated hypothyroid rats. In vivo administration of T2 led to an increase in PGC-1α protein levels in nuclei (transient) and mitochondria (longer lasting), suggesting a coordinate effect of T2 in these organelles that ultimately promotes net activation of mitochondrial biogenesis and BAT thermogenesis. The effect of T2 on PGC-1α is similar to that elicited by triiodothyronine. As a whole, the data reported here indicate T2 is a thyroid hormone derivative able to activate BAT thermogenesis

TRC150094 attenuates progression of nontraditional cardiovascular risk factors associated with obesity and type 2 diabetes in obese ZSF1 rats

Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for cardiovascular disease and type 2 diabetes mellitus. Moreover, individuals who have a triad of hypertension, dysglycemia, and elevated triglycerides along with reduced high-density lipoprotein cholesterol have a greater residual cardiovascular risk even after factoring for the traditional risk factors such as age, smoking, diabetes, and elevated low-density lipoprotein cholesterol. In our previous study we demonstrated that TRC150094, when administered to rats receiving a high-fat diet, stimulated mitochondrial fatty acid oxidation (FAO) and reduced visceral adiposity, opening an interesting perspective for a possible clinical application. In the present study, oral administration of TRC150094 to obese Zucker spontaneously hypertensive fatty rats (obese ZSF1) improved glucose tolerance and glycemic profile as well as attenuated a rise in blood pressure. Obese ZSF1 rats treated with TRC150094 also showed reduced hepatic steatosis, reduced progression of nephropathy, and improved skeletal muscle function. At the cellular level, TRC150094 induced a significant increase in mitochondrial respiration as well as an increased FAO in liver and skeletal muscle, ultimately resulting in reduced hepatic as well as total body fat accumulation, as evaluated by magnetic resonance spectroscopy and magnetic resonance imaging, respectively. If reproduced in humans, these results could confirm that TRC150094 may represent an attractive therapeutic agent to counteract multiple residual cardiovascular risk components

Akap1 deficiency promotes mitochondrial aberrations and exacerbates cardiac injury following permanent coronary ligation via enhanced mitophagy and apoptosis

A-kinase anchoring proteins (AKAPs) transmit signals cues from seven-transmembrane receptors to specific sub-cellular locations. Mitochondrial AKAPs encoded by the Akap1 gene have been shown to modulate mitochondrial function and reactive oxygen species (ROS) production in the heart. Under conditions of hypoxia, mitochondrial AKAP121 undergoes proteolytic degradation mediated, at least in part, by the E3 ubiquitin ligase Seven In-Absentia Homolog 2 (Siah2). In the present study we hypothesized that Akap1 might be crucial to preserve mitochondrial function and structure, and cardiac responses to myocardial ischemia. To test this, eight-week-old Akap1 knockout mice (Akap1(-/-)), Siah2 knockout mice (Siah2(-/-)) or their wild-type (wt) littermates underwent myocardial infarction (MI) by permanent left coronary artery ligation. Age and gender matched mice of either genotype underwent a left thoracotomy without coronary ligation and were used as controls (sham). Twenty-four hours after coronary ligation, Akap1(-/-) mice displayed larger infarct size compared to Siah2(-/-) or wt mice. One week after MI, cardiac function and survival were also significantly reduced in Akap1(-/-) mice, while cardiac fibrosis was significantly increased. Akap1 deletion was associated with remarkable mitochondrial structural abnormalities at electron microscopy, increased ROS production and reduced mitochondrial function after MI. These alterations were associated with enhanced cardiac mitophagy and apoptosis. Autophagy inhibition by 3-methyladenine significantly reduced apoptosis and ameliorated cardiac dysfunction following MI in Akap1(-/-) mice. These results demonstrate that Akap1 deficiency promotes cardiac mitochondrial aberrations and mitophagy, enhancing infarct size, pathological cardiac remodeling and mortality under ischemic conditions. Thus, mitochondrial AKAPs might represent important players in the development of post-ischemic cardiac remodeling and novel therapeutic targets

Omega 3 fatty acids and hepatic insulin resistance: focus on ER stress and mitochondrial dynamics markers

Omega 3 Poly-Unsaturated Fatty Acids (PUFA-ω3) have a protective and therapeutic role to prevent hepatic insulin resistance (IR). In this study, the protective effect was evaluated through: 1) hepatic insulin signaling pathway markers (phosphorylated protein kinase B on Ser473, pAKT/PKB); 2) endoplasmic reticulum (ER) stress marker (phosphorylated transcription factor p-eIF2α); 3) mitochondrial dynamics marker (Mitofusin 2, Mfn2). These parameters were evaluated into 3 Wistar rats groups, so treated for 6 weeks: 1- N rats, treated with a standard diet (10.6% fats); 2- L rats, treated with a high fat diet, rich in lard (40% fats); 3- F rats, treated with a high fat diet rich in fish oil, major PUFA-ω3 source (40% fats). Hepatic pAKT, p-eIF2α and Mfn2 levels were determined by western blotting analysis. L group exhibited hepatic insulin resistance (as showed by pAKT content) associated with ER stress (as showed by increased p-eIF2α content). Furthermore, we observed increased hepatic insulin sensitivity (as showed by reduced pAKT content) associated to ER stress reduction (reduced p-eIF2α content) in F group compared to L group. A fundamental role seems to be played by Mfn2, that increased in F vs L group, preventing not only mitochondrial integrity, but also eIF2α phosphorylation. In this way, fish oil may have positive effect in the prevention of ER stress and IR onset

Absence of UCP3 Influences mitochondrial functionality in brown adipose tissue.

Brown adipose tissue (BAT) expresses two uncoupling proteins, UCP1 and UCP3. While the physiological role played by UCP1 is quite well established, that of UCP3 has not been elucidated yet. To obtain further insight into this aspect, we evaluated the impact of the absence of this protein on BAT mitochondria. To this aim, we used 8 weeks old wild type (WT) and UCP3 knockout (KO) female mice, housed at thermoneutrality. We performed functional, molecular and histological analysis. The lack of UCP3 significantly reduces respiration rate of alpha-glycerophosphate energized mitochondria (when detected in basal condition, in the presence of GDP, as well as in the presence of FCCP) and the amplitude of membrane potential, thus indicating an inhibition of the respiratory chain activity. At the same time, the absence of UCP3 enhances both the percentage of electrons leaking from respiratory chain and reducing oxygen to superoxide, and the mitochondrial level of lipid hydroperoxides, i.e. two factors known to influence the activity of the respiratory chain complexes and their assembly in supercomplexes. In line with this possibility, our BN-PAGE-based analysis shows a significant inhibition of the in gel activities of both complex I and complex IV in mitochondria from BAT of UCP3 KO mice compared to WT controls. In addition the analysis of the electrophoretic profile of supercomplexes, obtained from digitonin-solubilized mitochondria, shows that mitochondria from UCP3 KO mice contain significant lower amount of specific respiratory supercomplexes, whose apparent molecular weight is between 800 kDa and 750 kDa. Moreover, in UCP3 KO mice, variations in mitochondrial functionality are also associated with alterations in mitochondrial morphology, as revealed by electron microscopy analysis. As a whole, these data indicate that in BAT UCP3 plays a significant role in influencing respiratory chain complexes activity and assembly, thus preserving mitochondrial functionality

Environmental Pollutants Effect on Brown Adipose Tissue

Brown adipose tissue (BAT) with its thermogenic function due to the presence of the mitochondrial uncoupling protein 1 (UCP1), has been positively associated with improved resistance to obesity and metabolic diseases. During recent years, the potential influence of environmental pollutants on energetic homoeostasis and obesity development has drawn increased attention. The purpose of this review is to discuss how regulation of BAT function could be involved in the environmental pollutant effect on body energy metabolism. We mainly focused in reviewing studies on animal models, which provide a better insight into the cellular mechanisms involved in this effect on body energy metabolism. The current literature supports the hypothesis that some environmental pollutants, acting as endocrine disruptors (EDCs), such as dichlorodiphenyltrichoroethane (DDT) and its metabolite dichlorodiphenylethylene (DDE) as well as some, traffic pollutants, are associated with increased obesity risk, whereas some other chemicals, such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA), had a reverse association with obesity. Noteworthy, the EDCs associated with obesity and metabolic disorders impaired BAT mass and function. Perinatal exposure to DDT impaired BAT thermogenesis and substrate utilization, increasing susceptibility to metabolic syndrome. Ambient particulate air pollutions induced insulin resistance associated with BAT mitochondrial dysfunction. On the other hand, the environmental pollutants (PFOS/PFOA) elicited a reduction in body weight and adipose mass associated with upregulation of UCP1 and increased oxidative capacity in brown-fat mitochondria. Further research is needed to better understand the physiological role of BAT in response to exposure to both obesogenic and anti-obesogenic pollutants and to confirm the same role in humans