Fernando Goglia - Academia.edu (original) (raw)

Papers by Fernando Goglia

Frontiers in endocrinology, 2018

Thyroid hormones significantly influence energy expenditure by affecting the activity of metaboli... more Thyroid hormones significantly influence energy expenditure by affecting the activity of metabolic active tissues, among which, mammalian brown adipose tissue (BAT) plays a significant role. For a long time, the modulation of BAT activity by 3,3',5-triiodo-l-thyronine (T3) has been ascribed to its direct actions on this tissue; however, recent evidence indicates that T3, by stimulating specific brain centers, activates the metabolism of BAT the sympathetic nervous system. These distinct mechanisms of action are not mutually exclusive. New evidence indicates that 3,5-diiodo-l-thyronine (3,5-T2), a thyroid hormone derivative, exerts thermogenic effects, by influencing mitochondrial activity in metabolically active tissues, such as liver, skeletal muscle, and BAT. At the moment, due to the absence of experiments finalized to render a clear cut discrimination between peripheral and central effects induced by 3,5-T2, it is not possible to exclude that some of the metabolic effects ex...

Frontiers in Physiology

′ ,5-triiodo-L-thyronine (T3) improves hepatic lipid accumulation by increasing lipid catabolism ... more ′ ,5-triiodo-L-thyronine (T3) improves hepatic lipid accumulation by increasing lipid catabolism but it also increases lipogenesis, which at first glance appears contradictory. Recent studies have shown that 3,5-diiodothyronine (T2), a natural thyroid hormone derivative, also has the capacity to stimulate hepatic lipid catabolism, however, little is known about its possible effects on lipogenic gene expression. Because genes classically involved in hepatic lipogenesis such as SPOT14, acetyl-CoA-carboxylase (ACC), and fatty acid synthase (FAS) contain thyroid hormone response elements (TREs), we studied their transcriptional regulation, focusing on TRE-mediated effects of T3 compared to T2 in rats receiving high-fat diet (HFD) for 1 week. HFD rats showed a marked lipid accumulation in the liver, which was significantly reduced upon simultaneous administration of either T3 or T2 with the diet. When administered to HFD rats, T2, in contrast with T3, markedly downregulated the expression of the above-mentioned genes. T2 downregulated expression of the transcription factors carbohydrate-response element-binding protein (ChREBP) and sterol regulatory element binding protein-1c (SREBP-1c) involved in activation of transcription of these genes, which explains the suppressed expression of their target genes involved in lipogenesis. T3, however, did not repress expression of the TRE-containing ChREBP gene but repressed SREBP-1c expression. Despite suppression of SREBP-1c expression by T3 (which can be explained by the presence of nTRE in its promoter), the target genes were not suppressed, but normalized to HFD reference levels or even upregulated (ACC), partly due to the presence of TREs on the promoters of these genes and partly to the lack of suppression of ChREBP. Thus, T2 and T3 probably act by different molecular mechanisms to achieve inhibition of hepatic lipid accumulation.

Journal of Endocrinology, 1996

The objective of the present study was to test in vivo the metabolic effects of 3,5-di-iodothyron... more The objective of the present study was to test in vivo the metabolic effects of 3,5-di-iodothyronine (3,5-T2) in unanesthetized and unrestrained male Sprague-Dawley rats. Amino acid and lipid metabolisms were investigated by breath tests using as tracers the 13C-carboxyl-labeled molecules of leucine, alpha-ketoisocaproic acid (KIC) and octanoic acid, in four different groups of rats: hypothyroid animals (receiving propylthiouracil (PTU) and iopanoic acid), hypothyroid animals treated with either a daily i.p. injection of 3,5-T2 (25 micrograms/100 g body weight), or tri-iodothyronine (T3) (1 microgram/100 g body weight), and control euthyroid animals receiving equivalent volumes of the vehicle solutions. Energy expenditure was measured by continuous monitoring of O2 consumption and CO2 production in these different groups. Daily energy expenditure was decreased by 30% in PTU-treated rats. The chronic treatments with 3,5-T2 and T3 restored daily energy expenditure to the control level. 13CO2 recovered in breath following the i.v. injection of octanoic acid-[1-13C] was decreased in hypothyroid animals compared with control animals (P < 0.05) and restored to control values by T3 and 3,5-T2 treatments. The 13CO2 recovered in breath after i.v. injection of leucine-[1-13C] was increased in PTU-treated compared with control animals (P < 0.05). Chronic treatment with either 3,5-T2 or T3 restored 13CO2 to control values. Excretion of 13CO2 recovered in breath following the i.v. injection of KIC-[1-13C] was increased in PTU-treated compared with control animals. Chronic treatments with either 3,5-T2 or T3 did not restore KIC decarboxylation. These results suggest that 3,5-T2 exerts metabolic effects on energy expenditure, on both lipid beta-oxidation and leucine metabolism in hypothyroid rats. We conclude that 3,5-T2 is a metabolically active iodothyronine.

FEBS Letters, 1999

We sought a correlation between rat skeletal muscle triiodothyronine (T3)-mediated regulation of ... more We sought a correlation between rat skeletal muscle triiodothyronine (T3)-mediated regulation of uncoupling protein-3 (UCP3) expression and mitochondrial activity. UCP3 mRNA expression increased strongly during the hypothyroid-hyperthyroid transition. The rank order of mitochondrial State 3 and State 4 respiration rates was hypothyroid 6 euthyroid 6 hyperthyroid. The State 4 increase may have been due to the increased UCP3 expression, as the proton leak kinetic was stimulated in the hypothyroid-hyperthyroid transition and a good correlation exists between the State 4 and UCP3 mRNA level. As a significant proportion of an organism's resting oxygen consumption is dedicated to opposing the proton leak, skeletal muscle mitochondrial UCP3 may mediate part of T3's effect on energy metabolism.

Pflügers Archiv : European journal of physiology, 2002

Muscular changes accompanying and/or promoting the rapid postnatal improvement of the thermogenic... more Muscular changes accompanying and/or promoting the rapid postnatal improvement of the thermogenic efficiency of shivering were investigated in piglets. Animals were obtained at birth or killed after 5 days at thermoneutrality (34-30 degrees C) or in the cold (24-15 degrees C), to stimulate intense shivering thermogenesis. Fast-twitch-glycolytic (longissimus lumborum) and slow-twitch-oxidative (rhomboid) muscles were prepared for electron microscopic examination and chemical measurements. Muscle-specific changes in energy stores and metabolism were observed after birth, including the switch from glycogen to lipids and variation of the lactate/pyruvate ratio corresponding to the progressive acquisition of the metabolic type of the mature muscles. There was major age-related and/or cold-induced development of the structures involved in excitation-contraction coupling (triadic profiles, +80% in the cold), oxidative metabolism (number of lipid droplets, +81% with age in the cold; number ...

Uncoupling protein 3 (UCP3) is a member of the mitochondrial carrier superfamily, preferentially ... more Uncoupling protein 3 (UCP3) is a member of the mitochondrial carrier superfamily, preferentially expressed in skeletal muscle. Its function is not fully understood and it is debated whether it uncouples oxidative phosphorylation as does UCP1 in brown adipose tissue. Recent evidences suggest a role for UCP3 in the £ux of fatty acids in and out mitochondria and their utilization in concert with mitochondrial thioesterase-1 (MTE-1). In fact, mice overexpressing muscle UCP3 also show high levels of MTE-1. Feno¢brate is a hypolipidemic drug that prevents body weight gain in diet-induced obese rats and enhances lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Because fatty acids and feno¢brate stimulate PPARs and in turn UCP3, we investigated whether UCP3 expression might be induced 'de novo' in situations of increased hepatic mitochondrial fatty acid utilization caused by a combined e¡ect of a high-fat diet and feno¢brate treatment. We also investigated whether Mte-1 expression and L L-oxidation were a¡ected. We show here that Ucp3 is induced in liver of feno¢brate-treated rats at the mRNA and protein level. Expression was restricted to hepatocytes and was unevenly distributed in the liver. No increase in cell proliferation, in£ammatory or ¢brotic responses was found. Mte-1 expression and mitochondrial L L-oxidation were upregulated. Thus, Ucp3 can be transactivated in tissues where it is normally silent and feno¢brate can attain this e¡ect in liver. The data demonstrate that UCP3 is involved in fatty acid utilization and support the notion that UCP3 and MTE-1 are linked within the same metabolic pathway. ß

Background/Aims: Mitochondrial dysfunction is central to the physiopathology of steatosis and /or... more Background/Aims: Mitochondrial dysfunction is central to the physiopathology of steatosis and /or non-alcoholic fatty liver disease. In this study on rats we investigated whether 3,5-diiodo-L-thyronine (T2), a biologically active iodothyronine, acting at mitochondrial level is able to reverse hepatic steatosis after its induction through a high-fat diet.

1. Although the first evidence of a relationship between the thyroid and metabolism was reported ... more 1. Although the first evidence of a relationship between the thyroid and metabolism was reported in 1895, the mechanism by which thyroid hormones influence resting metabolic rate in whole animals is still poorly understood. This paper reports an attempt to test whether diiodothyronines (T2s) and triiodothyronine (T3) have different roles in the control of resting metabolism (RM). 2. Changes in resting metabolic rate were measured in hypothyroid rats treated acutely (25 ,ug (100 g body weight)-) either with one of the T2s or with T3. Injection of T3 induced an increase of about 35% in RM that started 25-30 h after the injection and lasted until 5-6 days after the injection, the maximal value being observed at 50-75 h. The injection of Ts evoked a temporally different pattern of response. The increases in RM started 6-12 h after the injection, had almost disappeared after 48 h, and the maximal stimulation was observed at 28-30 h. 3. When actinomycin D (an inhibitor of protein synthesis) and T3 were given together, the stimulation of RM was almost completely abolished. The simultaneous injection of actinomycin D and either of the T s, on the other hand, did not cause any attenuation of the stimulation seen with the T2 s alone. 4. Following chronic treatment (3 weeks) with either T3 or T2s there was a stimulation of organ growth only after the administration of T3. 5. Chronic administration of either T2s or T3 to hypothyroid rats significantly enhanced the oxidative capacity of each of the tissues considered. In the case of T2s the stimulation was almost the same whether it was expressed as an increase in specific activity or total tissue activity. In the case of T3 the increases were, in the main, secondary to the hypertrophic or hyperplastic effect. 6. These results indicate that T2s and T3 exert different effects on RM. The effects of T2s are rapid and possibly mediated by their direct interaction with mitochondria. Those of T3 are slower and more prolonged, and at least partly attributable to a modulation of the cellularity of tissues that are metabolically very active.

Bioscience reports, 2002

Because of their central role in the regulation of energy-transduction, mitochondria, the major s... more Because of their central role in the regulation of energy-transduction, mitochondria, the major site of oxidative processes within the cell, are considered a likely subcellular target for the action that thyroid hormones exert on energy metabolism. However, the mechanism underlying the regulation of basal metabolic rate (BMR) by thyroid hormones still remains unclear. It has been suggested that these hormones might uncouple substrate oxidation from ATP synthesis, but there are no clear-cut data to support this idea. Two iodothyronines have been identified as effectors of the actions of thyroid hormones on energy metabolism: 3',3,5-triiodo-L-thyronine (T3) and 3,5-diiodo-L-thyronine (T2). Both have significant effects on BMR, but their mechanisms of action are not identical. T3 acts on the nucleus to influence the expression of genes involved in the regulation of cellular metabolism and mitochondria function; 3,5-T2, on the other hand, acts by directly influencing the mitochondri...

World journal of hepatology, Jan 27, 2014

Fatty liver or nonalcoholic fatty liver disease (NAFLD), a problem of increasing clinical signifi... more Fatty liver or nonalcoholic fatty liver disease (NAFLD), a problem of increasing clinical significance and prevalence worldwide, is associated with increased risk for the development of cirrhosis and hepatocellular carcinoma. Although several therapeutic approaches can be used in the context of NAFLD, dietary and physical activities are still the most frequently used strategies. Some pharmacological agents show promising results although no conclusions can be drawn from recent clinical trials. Thyroid hormones [THs; thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3)] coordinate a diverse array of physiological events during development and lipid/energy homeostasis and have some potentially therapeutic actions which include inducing weight loss, and lowering plasma cholesterol levels and tissue adiposity. The thyroid hormones exert their physiological effects by binding to specific nuclear receptors [thyroid hormone receptors (TR)] of which the TRβ isoform is liver specific and h...

Frontiers in physiology, 2014

In vertebrates and, specifically, in mammals, energy homeostasis is achieved by the integration o... more In vertebrates and, specifically, in mammals, energy homeostasis is achieved by the integration of metabolic and neuroendocrine signals linked to one another in an intricate network hierarchically responding to the tight modulating action of hormones among which thyroid hormones (THs) play a central role. At the cellular level, 3,5,3'-triiodo-L-thyronine (T3) acts mainly by binding to specific nuclear receptors (TRs) but actually it is becoming more and more evident that some T3- actions are independent of TRs and that other iodothyronines, such as 3,5-diiodo-L-thyronine (T2), affect energy metabolism and adiposity. In the postgenomic era, clinical and basic biological researches are increasingly benefiting from the recently developed new omics approaches including, among the others, proteomics. Considering the recognized value of proteins as excellent targets in physiology, the functional and simultaneous analysis of the expression level and the cellular localization of multipl...

The FASEB Journal, 2011

The worldwide prevalence of obesityassociated pathologies, including type 2 diabetes, requires th... more The worldwide prevalence of obesityassociated pathologies, including type 2 diabetes, requires thorough investigation of mechanisms and interventions. Recent studies have highlighted thyroid hormone analogs and derivatives as potential agents able to counteract such pathologies. In this study, in rats receiving a high-fat diet (HFD), we analyzed the effects of a 4-wk daily administration of a naturally occurring iodothyronine, 3,5-diiodo-L-thyronine (T2), on the gastrocnemius muscle metabolic/structural phenotype and insulin signaling. The HFD-induced increases in muscle levels of fatty acid translocase (3-fold; P<0.05) and TGs (2-fold, P<0.05) were prevented by T2 (each; P<0.05 vs. HFD). T2 increased insulin-stimulated Akt phosphorylation levels (ϳ2.5-fold; P<0.05 vs. HFD). T2 induced these effects while sparing muscle mass and without cardiac hypertrophy. T2 increased the muscle contents of fast/glycolytic fibers (2-fold; P<0.05 vs. HFD) and sarcolemmal glucose transporter 4 (3-fold; P<0.05 vs. HFD). Adipocyte differentiation-related protein was predominantly present within the slow/oxidative fibers in HFD-T2. In T2-treated rats (vs. HFD), glycolytic enzymes and associated components were up-regulated (proteomic analysis, significance limit: 2-fold; P<0.05), as was phosphofructokinase activity (by 1.3-fold; P<0.05), supporting the metabolic shift toward a more glycolytic phenotype. These results highlight T2 as a potential therapeutic approach to the treatment of diet-induced metabolic dysfunctions,5-Diiodo-L-thyronine prevents high-fat diet-induced insulin resistance in rat skeletal muscle through metabolic and structural adaptations. FASEB J. 25, 3312-3324 (2011). www.fasebj.org

The FASEB Journal, 2003

It is hypothesized that mitochondrial uncoupling proteins operate as carriers of fatty acid perox... more It is hypothesized that mitochondrial uncoupling proteins operate as carriers of fatty acid peroxide anions. This is assumed to result in electrophoretic extrusion of such anions from the inner to the outer leaflet of the inner mitochondrial membrane, being driven by membrane potential (mitochondrial interior negative). In this way, the inner leaflet is ridded of fatty acid peroxides that otherwise can form very aggressive oxidants damaging mitochondrial DNA, aconitase, and other mitochondrial matrix-localized components of vital importance. The steady-state concentration the fatty acid peroxides is known to be low. This explains why UCP2, 3, 4, and 5 are present in small amounts usually insufficient to make a large contribution to the H ؉ conductance of the mitochondrial membrane.-Goglia, F., Skulachev, V. P. A function for novel uncoupling proteins: antioxidant defense of mitochondrial matrix by translocating fatty acid peroxides from the inner to the outer membrane leaflet. FASEB J. 17, 1585-1591 (2003)

PPAR Research, 2010

Peroxisome proliferator-activated receptors (PPARs), which are known to regulate lipid homeostasi... more Peroxisome proliferator-activated receptors (PPARs), which are known to regulate lipid homeostasis, are tightly controlled by nutrient availability, and they control nutrient handling. In this paper, we focus on how nutrients control the expression and action of PPARs and how cellular signaling events regulate the action of PPARs in metabolically active tissues (e.g., liver, skeletal muscle, heart, and white adipose tissue). We address the structure and function of the PPARs, and their interaction with other nuclear receptors, including PPAR cross-talk. We further discuss the roles played by different kinase pathways, including the extracellular signal-regulated kinases/mitogen-activated protein kinase (ERK MAPK), AMP-activated protein kinase (AMPK), Akt/protein kinase B (Akt/PKB), and the NAD+-regulated protein deacetylase SIRT1, serving to control the activity of the PPARs themselves as well as that of a key nutrient-related PPAR coactivator, PPARγ coactivator-1α (PGC-1α). We also highlight how currently applied nutrigenomic strategies will increase our understanding on how nutrients regulate metabolic homeostasis through PPAR signaling.

Pflügers Archiv - European Journal of Physiology, 2011

Controversy exists on whether uncoupling protein 3 (UCP3) positively or negatively influences ins... more Controversy exists on whether uncoupling protein 3 (UCP3) positively or negatively influences insulin sensitivity in vivo, and the underlying signaling pathways have been scarcely studied. We studied how a progressive reduction in UCP3 expression (using UCP3 +/+, UCP3 +/−, and UCP3 −/− mice) modulates insulin sensitivity and related metabolic parameters. In order to further validate our observations, we also studied animals in which insulin resistance was induced by administration of a high-fat diet (HFD). In UCP3 +/− and UCP3 −/− mice, gastrocnemius muscle Akt/protein kinase B (Akt/PKB) (serine 473) and AMP-activated protein kinase (AMPK) (threonine 171) phosphorylation, and glucose transporter 4 (GLUT4) membrane levels were reduced compared to UCP3 +/+ mice. The HOMA-IR index (insulin resistance parameter) was increased both in the UCP3 +/− and UCP3 −/− mice. In these mice, insulin administration normalized Akt/PKB phosphorylation between genotypes while AMPK phosphorylation was further reduced, and sarcolemmal GLUT4 levels were induced but did not reach control levels. Furthermore, non-insulin-stimulated muscle fatty acid oxidation and the expression of several involved genes both in muscle and in liver were reduced. HFD administration induced insulin resistance in UCP3 +/+ mice and the aforementioned parameters resulted similar to those of chow-fed UCP3 +/− and UCP3 −/− mice. In conclusion, high-fat-diet-induced insulin resistance in wild-type mice mimics that of chow-fed UCP3 +/− and UCP3 −/− mice showing that progressive reduction of UCP3 levels results in insulin resistance. This is accompanied by decreased fatty acid oxidation and a less intense Akt/PKB and AMPK signaling.

Journal of Proteomics, 2009

We defined the transcriptomic and proteomic profiles of rat ageing skeletal muscle using a combin... more We defined the transcriptomic and proteomic profiles of rat ageing skeletal muscle using a combined cDNA array, 2D-and Blue native-PAGE approach. This was allowed to obtain an overview of the interrelated events leading to the transcriptome/proteome/mitoproteome changes likely to underlie the structural/metabolic features of aged skeletal muscle. The main differences were found in genes/proteins related to energy metabolism, mitochondrial pathways, myofibrillar filaments, and detoxification. Concerning the abundance of mitochondrial OXPHOS complexes as well as their supramolecular organization and activity, mitochondria from old rats, when compared with those from young rats, contained significantly lower amounts of complex I (NADH:ubiquinone oxidoreductase), V (FoF1-ATP synthase), and III (ubiquinol:cytochrome c oxidoreductase). The same mitochondria contained a significantly larger amount of complex II (succinate:ubiquinone oxidoreductase), but an unchanged amount of complex IV (cytochrome c oxidase, COX). When comparing the supercomplex profiles between young and old muscle mitochondria, the densitometric analysis revealed that lighter supercomplexes were significantly reduced in older mitochondria, and that in the older group the major supercomplex bands were those representing heavier supercomplexes, likely suggesting a compensatory mechanism that, in ageing muscle, is functionally directed towards substrate channeling and catalytic enhancement advantaging the respirosome.

Journal of Hepatology, 2011

Previous studies have demonstrated that 3,5-L-diiodothyronine (T 2 ) is able to prevent lipid acc... more Previous studies have demonstrated that 3,5-L-diiodothyronine (T 2 ) is able to prevent lipid accumulation in the liver of rats fed a high-fat diet. Whether this effect is due to a direct action of T 2 on the liver has not been elucidated. In this study, we investigated the ability of T 2 to reduce the excess lipids in isolated hepatocytes treated with fatty acids (FFAs). The effects of T 2 were compared with those elicited by 3,3 0 ,5-L-triiodothyronine (T 3 ). Methods: To mimic the fatty liver condition, primary cultures of rat hepatocytes were overloaded with lipids, by exposure to FFAs (''fatty hepatocytes''), and then treated with T 2 or T 3 . Lipid content, morphometry of lipid droplets (LDs), and expression of the adipocyte differentiation-related protein (ADRP) and the peroxisome proliferator-activated receptors (PPAR-a, -c, -d) were evaluated. Activities of the lipolytic enzyme acyl CoA oxidase -AOX and the antioxidant enzymes superoxide dismutase -SOD and catalase -CAT were also determined. Results: FFA-induced lipid accumulation was associated with an increase in both number/size of LDs and expression of ADRP, PPAR-c, and PPAR-d/b mRNAs, as well as in the activities of AOX, SOD, and CAT. The addition of T 2 or T 3 to ''fatty hepatocytes'' resulted in a reduction in: (i) lipid content and LD diameter; (ii) PPAR-c and PPAR-d expression; (iii) activities of AOX and antioxidant enzymes. Conclusions: These data demonstrate, for the first time, a direct action of both T 2 and T 3 in reducing the excess fat in cultured hepatocytes. Ó

Diabetes, Metabolic Syndrome and Obesity: Targets and Therapy, 2011