Energy , evolution , and human diseases : an overview 1 – 4

In the symposium entitled “Transcriptional controls of energy sensing,” the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1a (peroxisome proliferatoractivated receptor c co-activator 1a), a transcriptional co-activator that has powerful effects on mitochondria; 3) methylation and demethylation in response to metabolic fluctuations; and 4) FGF21 (fibroblast growth factor 21) as an emerging hormone-like intercellular metabolic coordinator. This introduction places these advances within a broad overview of energy sensing and energy balance, with a focus on human evolution and disease. Four key elements of human biology are analyzed: 1) elevated body temperature; 2) complex prolonged reproductive pathways; 3) emergence of 4 large, well-defined fat depots, each with its own functional role; and 4) an immune system that is often up-regulated by nutrition-related signals, independent of the actual presence of a pathogen. We propose that an overactive immune system, including the “metabolic syndrome,” was adopted evolutionarily in the distant past to help hold out against unconquerable infections such as tuberculosis, malaria, and trypanosomiasis. This immune activation is advantageous in the absence of other disease management methods, especially under conditions in which life expectancy is short. The inflammation has become a major agent of pathology in wealthy populations in whom the pathogens are a minor threat and life expectancy is long. The “Conclusions” section sketches cautiously how understanding the molecules involved in energy sensing and energy balance may lead to specific therapies for obesity and diabetes and for their complications. Am J Clin Nutr 2011;93(suppl):875S–83S. ENERGY SENSING AND ENERGY BALANCE This symposium, entitled “Transcriptional controls of energy sensing,” brings together experts on the rapid advances that are being made in understanding how energy needs of the body are sensed, registered, and fulfilled. This overview will link the recognition of energy needs to energy balance in each cell and in the whole body. A surprisingly large number of close links and important overlaps between energy-related processes and the body’s immune defense system have been recognized recently. The effects are especially prominent in people who are overweight. Consideration of the evolutionary forces that may have driven the intertwining of the 2 systems (energy balance and antimicrobial defenses) will encourage a broader appreciation of the studies presented by our 4 invited experts. Applications to metabolic disease states and potential therapies conclude this overview. EMBARKATION Managing energy—the amount and distribution—is a complex and highly regulated process with many built-in safeguards (1). Each individual performs an awe-inspiring balancing of the books over the course of a lifetime, on an annual basis and on a daily basis, while providing energy for all of his or her activities. In a world in which the 4-minute mile—1mile run in 4 minutes— is considered to be outstanding, how does the whole body of a marathon champion manage to travel 26 consecutive 5-minute miles? Even that performance is dimmed by our relatives, the arctic birds who fly 7000 miles over the ocean in 11 days without stopping for rest or food. Not only does overall intake keep in step with overall consumption, but every one of the tens of trillions of cells in the body closes its 24-hour day in nutritional balance, right where it started. Each cardiac myocyte finds the energy to beat once every second from early embryonic life right up to last breath of life in old age. Every individual cell needs to manage its energy budget to meet its basic housekeeping needs and its specialized needs. Each invited expert in the symposium will elucidate this remarkable process by focusing on one step that is critical for maintaining intracellular energy balance. Addressing this challenge, Hardie describes one key enzyme (2), Fernandez-Marcos and Auwerx present one very important transcription co-activator (3), Barres and Zierath describe an overall process of regulating gene expression (4), and Domouzoglou and Maratos-Flier report on one hormone-like intercellular messenger that helps the organism to distribute energy optimally (5). Each of these is representative of the ways that energy is managed at the cellular level and hints at the complexity of the coordination. 1 From the Feinstein Institute for Medical Research, Elmezzi Graduate School of Molecular Medicine, North Shore-Long Island Jewish Health System, Manhasset, NY (JR and ALS); Hofstra North Shore-LIJ School of Medicine, Hempstead, NY (JR); Albert Einstein College of Medicine, Yeshiva University, Bronx, NY (JR); the Division of Endocrinology, Diabetes, and Metabolism, New York University Medical Center, New York, NY (AD): and the VA New York Harbor HeaIthcare System, New York, NY (AD). 2 The funding organizations had no role in the preparation, review, or approval of the manuscript. 3 JR’s academic program receives financial support from the Feinstein Institute for Medical Research, Manhasset, NY; Russell Berrie Foundation, Teaneck, NJ; and the Alan and Tatyana Forman family. 4 Address correspondence to J Roth, 149-37 Powells Cove Boulevard, Whitestone NY 11357. E-mail: jesserothmd@hotmail.com. First published online February 2, 2011: doi: 10.3945/ajcn.110. 001909. Am J Clin Nutr 2011;93(suppl):875S–83S. Printed in USA. 2011 American Society for Nutrition 875S D ow naded rom http/academ ic.p.com /ajcn/article-t/93/4/875S/4597797 by gest on 05 M arch 2019 AMP-activated protein kinase In his article, Hardie (2) introduces AMP-activated protein kinase (AMPK) as a major energy sensor in cells throughout the body. It is activated when the AMP/ATP ratio in the cell rises—ie, because ATP production slackens, ATP consumption is accelerated, or both. In this way, AMPK also acts to sense glucose deprivation and, in a grander way, impending starvation at the cellular level. It activates catabolic (ATP-generating) pathways and impedes ATP-consuming processes. Hardie reminds us that the mitochondria are heavily influenced by AMPK and that AMPK is the site of action of metformin, one of the most widely used antidiabetes agents, and of resveratrol, an ingredient of red wine that is one of the most highly touted natural agents.