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Research Programmes

Molecular Medicine

Molecular pathology and therapy in heterogenic and polygenic diseases

Antonio Zorzano

Antonio Zorzano

Group Leader
Professor (Biochemistry and Molecular Biology Dept. - UB)
Office Tel : +34 93 40 37197
Lab Tel : +34 93 403 47 01
e-mail : antonio.zorzanoirbbarcelona.org

Background

It has been estimated that between 200 million and 300 million people worldwide will meet World Health Organization diagnostic criteria for diabetes mellitus by the end of this decade. This epidemic of predominantly type 2 diabetes has been mediated largely by our shift toward a more sedentary lifestyle, which predisposes us to obesity and insulin resistance. Individuals affected by this disease may also exhibit an array of associated undesirable effects such as hypertension, dyslipidemia, and hypercoagulability, which lead to morbidity and mortality from atherosclerotic vascular disease. The co-existence of several of these disorders with insulin resistance constitutes the metabolic syndrome. In Western society, metabolic syndrome diseases are growing at epidemic rates and currently affect about 20% of the general population and over 40% of people over 60 years of age. Recent epidemiological and biological data indicate that the etiology of these diseases may share unexpected and common genetic and biochemical mechanisms. A major step towards understanding the metabolic syndrome is the identification of susceptibility genes, which may lead to the acquisition of additional therapeutic targets for future drug design.

Research Interests

We aim to determine the molecular mechanisms involved in the development of insulin resistance and, in particular, to identify novel obesity and type 2 diabetes susceptibility genes.

This general objective is structured into three levels:

  1. Identification of genes responsible for the development of insulin resistance associated with obesity or type 2 diabetes, with special emphasis on those genes implicated in novel mechanisms involving mitochondrial processes (i.e., mitochondrial dynamics), encoding proteins involved in the regulation of nuclear gene expression, or encoding proteins involved in novel signalling events.
  2. Analysis of the molecular mechanisms involved in the regulation of glucose transport in muscle and adipose cells and in the development of lipotoxicity.
  3. Identification of novel targets and development of new compounds for the treatment of the metabolic syndrome.
Research Lines

Our research group is organized around 3 research lines:

1. Identification of genes responsible for the development of insulin resistance, obesity or type 2 diabetes.

Our laboratory has reported the implication of the bi-functional protein SSAO/VAP-1 (semicarbazide-sensitive amine oxidase/vascular adhesion protein-1) in the regulation of glucose transport in adipose cells. Manipulation of SSAO activity reverses insulin resistance and hyperglycemia in diabetic rats. Furthermore, SSAO/VAP-1 is cleaved from the plasma membrane in response to factors such as TNFα, and the soluble resultant form (soluble SSAO) is released to the circulation. In keeping with this, the plasma concentration of soluble SSAO increases in insulin resistant states. On the basis of these data, at present we are studying the functional role of SSAO/VAP1 in knock-out mice and the specific role of the soluble form of SSAO and its relationship with insulin resistance. We have identified a nuclear gene that encodes the mitochondrial protein mitofusin-2 (Mfn2).

We have demonstrated that Mfn2 regulates mitochondrial fusion as well as mitochondrial metabolism. In addition, we have also shown that Mfn2 gene expression is repressed in skeletal muscle of obese or type 2 diabetic subjects. All these findings indicate that Mfn2 may be involved in the pathophysiology of obesity and type 2 diabetes. We are currently examining the possible role of of Mfn2 in the development of traits of the metabolic syndrome in humans and also the specific mechanisms by which Mfn2 regulates mitochondrial metabolism.

Furthermore, we have identified several genes that encode nuclear proteins with altered expression in obesity and/or type 2 diabetes. Our current research addresses the functional role of these genes and their possible implication as susceptibility factors for type 2 diabetes or in the development of the metabolic syndrome.

2. Analysis of the molecular mechanisms involved in the regulation of glucose transport in muscle and adipose cells and in the development of lipotoxicity.

We address the delineation of intracellular signalling mechanisms that cause the rapid translocation of GLUT4 glucose transporters from an intracellular localization to the cell surface as well as the molecular machinery that causes cell lipotoxicity. In this regard, our research activities explore the signalling pathways involved in the metabolic effects of muscle contraction and specifically in the mechanisms implicated in GLUT4 recruitment to the cell surface. In addition, and on the basis of the recent observations that caveolin-1 and caveolae are involved in integrity and function of the lipid droplet and in binding, transport, and storage of fatty acids and insulin action, we aim to define the role of caveolin-1/caveolae in the mechanisms by which the adipocyte efficiently packages and stores TAG in distinct adipose depots. These studies may reveal the underlying causes of obesity- or lipodystrophy-associated lipotoxicity.

3. Identification of novel targets and development of new compounds for the treatment of the metabolic syndrome.

We have demonstrated that the use of SSAO/VAP-1 substrates and low doses of vanadate potently stimulate glucose transport in adipocytes. In addition, the in vivo administration of these compounds exerts an anti-diabetic action in animal models of diabetes. On the basis of these studies, and in collaboration with Fernando Albericio (IRB Barcelona) and Miriam Royo (PCB), we have generated a novel class of compounds, namely arylalkylamine vanadium salts, which, when administered orally or subcutaneously, also show very potent anti-diabetic activity in animals. We are currently studying the toxicological and pharmacological properties of this class of compounds, and their possible application in the treatment of traits of the metabolic syndrome.

Funding

This group receives financial support from the following sources:

  • Generalitat de Catalunya (Government of Catalonia)
  • Instituto de Salud Carlos III, Ministerio de Sanidad y Consumo (Spanish National Institute of Health)
  • Ministerio de Educación y Ciencia (Spanish Ministry of Science & Education)
  • European Commission
Highlighted Projects
  • Integration of the system models of mitochondrial function and insulin signalling and its application in the study of complex diseases (MITIN); Contract no. 223450; www.mitin-fp7.eu
  • Cooperación transnacional para la innovación tecnológica en el desarrollo de moléculas para el tratamiento de la obesidad y la diabetes (DIOMED); Contract no. DIOMED-SOE1/P1/E178; http://diomed-sudoe.eu/front
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Institute for Research in Biomedicine (IRB Barcelona)
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C/ Baldiri Reixac 10
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