title: Regulatory principles in metabolism-then and now.
abstract: The importance of metabolic pathways for life and the nature of participating reactions have challenged physiologists and biochemists for over a hundred years. Eric Arthur Newsholme contributed many original hypotheses and concepts to the field of metabolic regulation, demonstrating that metabolic pathways have a fundamental thermodynamic structure and that near identical regulatory mechanisms exist in multiple species across the animal kingdom. His work at Oxford University from the 1970s to 1990s was groundbreaking and led to better understanding of development and demise across the lifespan as well as the basis of metabolic disruption responsible for the development of obesity, diabetes and many other conditions. In the present review we describe some of the original work of Eric Newsholme, its relevance to metabolic homoeostasis and disease and application to present state-of-the-art studies, which generate substantial amounts of data that are extremely difficult to interpret without a fundamental understanding of regulatory principles. Eric's work is a classical example of how one can unravel very complex problems by considering regulation from a cell, tissue and whole body perspective, thus bringing together metabolic biochemistry, physiology and pathophysiology, opening new avenues that now drive discovery decades thereafter.
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Rui
authors.initials: R
authors.lastname: Curi
authors.affiliation: School of Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6845, Australia philip.newsholme@curtin.edu.au.
authors.forename: Philip
authors.initials: P
authors.lastname: Newsholme
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Gabriel Nasri
authors.initials: GN
authors.lastname: Marzuca-Nassr
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Hilton Kenji
authors.initials: HK
authors.lastname: Takahashi
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil.
authors.forename: Sandro Massao
authors.initials: SM
authors.lastname: Hirabara
authors.affiliation: Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, SP, Brazil School of Biomedical Sciences, Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6845, Australia.
authors.forename: Vinicius
authors.initials: V
authors.lastname: Cruzat
authors.affiliation: Laboratory of Cellular Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Krause
authors.affiliation: Laboratory of Cellular Physiology, Institute of Basic Health Sciences, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil.
authors.forename: Paulo Ivo Homem
authors.initials: PI
authors.lastname: de Bittencourt
mesh_terms: D000818:Animals; D006706:Homeostasis; D006801:Humans; D008660:Metabolism / Q000235:genetics / Q000502:physiology*; D008954:Models, Biological; D013816:Thermodynamics
keywords: flux control; futile cycles; metabolic pathways; substrate cycles