RICERCA ITALIANA     

CELLULAR AND MOLECULAR MECHANISMS INVOLVED IN THE METABOLIC HOMEOSTASIS: PHYSIO-PATHOLOGICAL ASPECTS.

Università degli Studi del Sannio di Benevento

Abstract

Energy homeostasis,a part of metabolic homeostasis, comprises three distinct but integrated factors: energy intake, energy expenditure(with associated network of biochemical pathways)and related endocrine apparatus. Any dissociation between these factors may lead to physiological dysfunctions that usually evolve toward pathological conditions such as, among the others, obesity.Indeed, obesity represents a situation of altered energy homeostasis characterized by fat accumulation in adipose tissues as well as in ectopic site of storage such as liver (steatosis) and skeletal muscle. Due to this, the scientists are now searching for treatments able to increase energy expenditure which presupposes a deep knowledge of the cellular mechanisms and the specific tissues involved in metabolic homeostasis. Part of these topics is still largely unknown. Metabolic processes are affected by numerous hormones and in the present project a great effort is devoted to the role played by iodothyronines (T3, T2) in these processes. It is a historical notion that T3 affects thermogenesis and energy expenditure but, interestingly, it has been recently demonstrated that also T2 (so far considered an inactive deiodinated product of T3) is able to stimulate energy metabolism. Mitochondria, on the other hand, play a central role in energy transduction and their contribution depends on their morphology (e.g. volume is a limiting-factor for their activity) and the recent discovery of the presence of >>>

Principal Investigator

Fernando GOGLIA Università degli Studi del SANNIO di BENEVENTO

Research Objectives

The objective of the research planned to carry out in this project is to shed light on some molecular and cellular mechanisms involved in the metabolic homeostasis in both physiological and pathological situations, bringing into play tissues and systems such as the liver, skeletal muscle, adipose tissue and the endocrine system. In addition, it is anticipated to obtain viable information on some mechanisms involved in the energy homeostasis of the whole organism. This is relevant, also considering the ever growing interest of the scientific world in the problems surrounding metabolic disturbances (e.g. obesity, dislipidemie etc), leading to an ever growing number of social problems.Some findings hovewer have opened interesting perspectives in this field.In particular: 1) the discovery of UCP3 ( a protein involved in some relevant aspects of mitochondrial metabolism) in the skeletal muscle of animals including humans 2) the discovery that T2 (a deiodinated product of T3,in the past and to a large extent now, regarded as biologically inactive) is a compound capable of stimulating energy metabolism , 3) the discovery of AQP8 in the mitochondria, and, thus, the possibility that the latter may be involved in the homeostatic mechanisms of these organelles. Thyroid hormones are well known both to stimulate metabolism and (at the same time) to lower metabolic efficiency. This effect has long been the focus of research into the potential use of T3 as a drug to stimulate weight-loss >>>

First Results

On the basis of what described above, we predict to clarify or obtain important information about the cellular and molecular mechanisms involved in the metabolic homeostasis both in physiological and in pathological conditions. We hope to obtain results leading to establish: 1)the effect of T2 on body adiposity both in rats and humans; 2)the efficacy of T2 in reducing serum levels of LDL, triglycerides and counteract liver steatosis in humans and rats; 3)the ability of T2 to counteract alcohol-induced damage in steatosic liver and to positively affect fatty-liver regeneration after partial hepatoctomie; 4) the biochemical mechanisms involved in the effect of T2 and its cellular targets in liver and adipose tissues; 5) the pathways through which T3 affects UCP3 expression; 6) the correlation existing between UCP3 expression, substrates metabolism and muscle fiber type composition; 7) the role of liver and skeletal muscle mitochondria in metabolic homeostasis; 8) the possibility that AQP8 is involved in the movement of water, small electrolyte and anelectrolyte metabolites across the IMM; 9) the regulation by hormones of AQP8 expression in mitochondria;10) the possible interactions of AQP8 with the PTP.

Timescale

24 months

National and international background

Metabolism, the mechanism of living cells to obtain, convert and store materia and energy from nutrients, is a complex network of chemical reactions within the cell that is constituted by several biochemical pathways. Metabolic pathways can be controlled at three levels. First: gene expression, translation, and protein turnover. Second: the catalytic activity of enzymes (i.e by allosteric modulators, activators and competitive inhibitors) and post-translational modifications (such as phosphorylation, acetylation, and glycosylation) usually under the control of hormones, growth-factors, and neurotransmitters. Third: substrate availability, usually controlled by steady-state equilibrium and compartimentalization. The latter depends on active membrane transport systems and the passive diffusion via substrate specific membrane proteins.
Contrary to the objects of physics, biological systems are complex in their composition, asymmetric in structure, and the flow of energy and chemical reactions never at equilibrium. Yet, organisms maintain a stable structure over long periods of time. This stability of large structures with the molecular components constantly replaced and regenerated is called homeostasis, meaning they maintain a "status quo". Living organisms maintain a state of metabolic homeostasis which can be viewed as a steady-state throughput of energy to sustain body function, structure, and information. As a consequence we can state that metabolism is a >>>