Pieter De Lange

Publications (57) View all

• Article: Responses of skeletal muscle lipid metabolism in rat gastrocnemius to hypothyroidism and iodothyronine administration: a putative role for FAT/CD36.

  Assunta Lombardi, Rita de Matteis, Maria Moreno, Laura Napolitano, Rosa Anna Busiello, Rosalba Senese, Pieter de Lange, Antonia Lanni, Fernando Goglia
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  ABSTRACT: Iodothyronines such as triiodothyronine (T3) and 3,5-diiodothyronine (T2) influence energy expenditure and lipid metabolism. Skeletal muscle contributes significantly to energy homeostasis, and the above iodothyronines are known to act on this tissue. However, little is known about the cellular/molecular events underlying the effects of T3 and T2 on skeletal muscle lipid handling. Since FAT/CD36 is involved in the utilization of free fatty acids by skeletal muscle -- specifically, in their import into that tissue and presumably their oxidation at the mitochondrial level -- we hypothesized that related changes in lipid handling and in FAT/CD36 expression and subcellular redistribution would occur due to hypothyroidism and to T3 or T2 administration to hypothyroid rats. In gastrocnemius muscles isolated from hypothyroid rats, FAT/CD36 was upregulated (mRNA levels, and total tissue, sarcolemmal, and mitochondrial protein levels). Administration of either T3 or T2 to hypothyroid rats resulted in: i) little or no change in FAT/CD36 mRNA level, ii) a decreased total FAT/CD36 protein level, and iii) further increases in FAT/CD36 protein level in sarcolemma and mitochondria. Thus, the main effect of each iodothyronine seemed to be exerted at the level of FAT/CD36 cellular distribution. Effect (iii) was already evident at 1h after iodothyronine administration. Each iodothyronine increased the mitochondrial fatty acid oxidation rate. However, the mechanisms underlying their rapid effects seem to differ: T2 and T3 each induce FAT/CD36 translocation to mitochondria, but only T2 induces increases in carnitine-palmitoyl-transferase system activity and in the mitochondrial substrate-oxidation rate.
  AJP Endocrinology and Metabolism 09/2012; · 4.75 Impact Factor
• Article: Metabolic effects of the iodothyronine functional analogue TRC150094 on the liver and skeletal muscle of high-fat diet fed overweight rats: an integrated proteomic study.

  Elena Silvestri, Daniela Glinni, Federica Cioffi, Maria Moreno, Assunta Lombardi, Pieter de Lange, Rosalba Senese, Michele Ceccarelli, Anna Maria Salzano, Andrea Scaloni, Antonia Lanni, Fernando Goglia
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  ABSTRACT: A novel functional iodothyronine analogue, TRC150094, which has a much lower potency toward thyroid hormone receptor (α1/β1) activation than triiodothyronine, has been shown to be effective at reducing adiposity in rats simultaneously receiving a high-fat diet (HFD). Here, by combining metabolic, functional and proteomic analysis, we studied how the hepatic and skeletal muscle phenotypes might respond to TRC150094 treatment in HFD-fed overweight rats. Drug treatment increased both the liver and skeletal muscle mitochondrial oxidative capacities without altering mitochondrial efficiency. Coherently, in terms of individual respiratory in-gel activity, blue-native analysis revealed an increased activity of complex V in the liver and of complexes II and V in tibialis muscle in TCR150094-treated animals. Subsequently, the identification of differentially expressed proteins and the analysis of their interrelations gave an integrated view of the phenotypic/metabolic adaptations occurring in the liver and muscle proteomes during drug treatment. TRC150094 significantly altered the expression of several proteins involved in key liver metabolic pathways, including amino acid and nitrogen metabolism, and fructose and mannose metabolism. The canonical pathways most strongly influenced by TRC150094 in tibialis muscle included glycolysis and gluconeogenesis, amino acid, fructose and mannose metabolism, and cell signaling. The phenotypic/metabolic influence of TRC150094 on the liver and skeletal muscle of HFD-fed overweight rats suggests the potential clinical application of this iodothyronine analogue in ameliorating metabolic risk parameters altered by diet regimens.
  Molecular BioSystems 04/2012; 8(7):1987-2000. · 3.53 Impact Factor
• Article: Nonthyrotoxic prevention of diet-induced insulin resistance by 3,5-diiodo-L-thyronine in rats.

  Pieter de Lange, Federica Cioffi, Rosalba Senese, Maria Moreno, Assunta Lombardi, Elena Silvestri, Rita De Matteis, Lillà Lionetti, Maria Pina Mollica, Fernando Goglia, Antonia Lanni
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  ABSTRACT: High-fat diets (HFDs) are known to induce insulin resistance. Previously, we showed that 3,5-diiodothyronine (T2), concomitantly administered to rats on a 4-week HFD, prevented gain in body weight and adipose mass. Here we investigated whether and how T2 prevented HFD-induced insulin resistance. We investigated the biochemical targets of T2 related to lipid and glucose homeostasis over time using various techniques, including genomic and proteomic profiling, immunoblotting, transient transfection, and enzyme activity analysis. Here we show that, in rats, HFD feeding induced insulin resistance (as expected), whereas T2 administration prevented its onset. T2 did so by rapidly stimulating hepatic fatty acid oxidation, decreasing hepatic triglyceride levels, and improving the serum lipid profile, while at the same time sparing skeletal muscle from fat accumulation. At the mechanistic level, 1) transfection studies show that T2 does not act via thyroid hormone receptor β; 2) AMP-activated protein kinase is not involved in triggering the effects of T2; 3) in HFD rats, T2 rapidly increases hepatic nuclear sirtuin 1 (SIRT1) activity; 4) in an in vitro assay, T2 directly activates SIRT1; and 5) the SIRT1 targets peroxisome proliferator-activated receptor (PPAR)-γ coactivator (PGC-1α) and sterol regulatory element-binding protein (SREBP)-1c are deacetylated with concomitant upregulation of genes involved in mitochondrial biogenesis and downregulation of lipogenic genes, and PPARα/δ-induced genes are upregulated, whereas genes involved in hepatic gluconeogenesis are downregulated. Proteomic analysis of the hepatic protein profile supported these changes. T2, by activating SIRT1, triggers a cascade of events resulting in improvement of the serum lipid profile, prevention of fat accumulation, and, finally, prevention of diet-induced insulin resistance.
  Diabetes 09/2011; 60(11):2730-9. · 8.29 Impact Factor
• Article: 3,5-Diiodo-L-thyronine prevents high-fat-diet-induced insulin resistance in rat skeletal muscle through metabolic and structural adaptations.

  Maria Moreno, Elena Silvestri, Rita De Matteis, Pieter de Lange, Assunta Lombardi, Daniela Glinni, Rosalba Senese, Federica Cioffi, Anna Maria Salzano, Andrea Scaloni, Antonia Lanni, Fernando Goglia
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  ABSTRACT: The worldwide prevalence of obesity-associated 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 (∼2.5-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.
  The FASEB Journal 06/2011; 25(10):3312-24. · 5.71 Impact Factor
• Source

  Available from: Antonia Lanni

  Article: Studies of complex biological systems with applications to molecular medicine: the need to integrate transcriptomic and proteomic approaches.

  Elena Silvestri, Assunta Lombardi, Pieter de Lange, Daniela Glinni, Rosalba Senese, Federica Cioffi, Antonia Lanni, Fernando Goglia, Maria Moreno
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  ABSTRACT: Omics approaches to the study of complex biological systems with potential applications to molecular medicine are attracting great interest in clinical as well as in basic biological research. Genomics, transcriptomics and proteomics are characterized by the lack of an a priori definition of scope, and this gives sufficient leeway for investigators (a) to discern all at once a globally altered pattern of gene/protein expression and (b) to examine the complex interactions that regulate entire biological processes. Two popular platforms in "omics" are DNA microarrays, which measure messenger RNA transcript levels, and proteomic analyses, which identify and quantify proteins. Because of their intrinsic strengths and weaknesses, no single approach can fully unravel the complexities of fundamental biological events. However, an appropriate combination of different tools could lead to integrative analyses that would furnish new insights not accessible through one-dimensional datasets. In this review, we will outline some of the challenges associated with integrative analyses relating to the changes in metabolic pathways that occur in complex pathophysiological conditions (viz. ageing and altered thyroid state) in relevant metabolically active tissues. In addition, we discuss several new applications of proteomic analysis to the investigation of mitochondrial activity.
  Journal of Biomedicine and Biotechnology 01/2011; 2011:810242. · 2.44 Impact Factor