Energy, evolution, and human diseases: an overview.

In the symposium entitled "Transcriptional controls of energy sensing," the authors presented recent advances on 1) AMP kinase, an intracellular energy sensor; 2) PGC-1α (peroxisome proliferator-activated receptor γ co-activator 1α), 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.