title: Metabolism as a tool for understanding human brain evolution: lipid energy metabolism as an example.
abstract: Genes and the environment both influence the metabolic processes that determine fitness. To illustrate the importance of metabolism for human brain evolution and health, we use the example of lipid energy metabolism, i.e. the use of fat (lipid) to produce energy and the advantages that this metabolic pathway provides for the brain during environmental energy shortage. We briefly describe some features of metabolism in ancestral organisms, which provided a molecular toolkit for later development. In modern humans, lipid energy metabolism is a regulated multi-organ pathway that links triglycerides in fat tissue to the mitochondria of many tissues including the brain. Three important control points are each suppressed by insulin. (1) Lipid reserves in adipose tissue are released by lipolysis during fasting and stress, producing fatty acids (FAs) which circulate in the blood and are taken up by cells. (2) FA oxidation. Mitochondrial entry is controlled by carnitine palmitoyl transferase 1 (CPT1). Inside the mitochondria, FAs undergo beta oxidation and energy production in the Krebs cycle and respiratory chain. (3) In liver mitochondria, the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) pathway produces ketone bodies for the brain and other organs. Unlike most tissues, the brain does not capture and metabolize circulating FAs for energy production. However, the brain can use ketone bodies for energy. We discuss two examples of genetic metabolic traits that may be advantageous under most conditions but deleterious in others. (1) A CPT1A variant prevalent in Inuit people may allow increased FA oxidation under nonfasting conditions but also predispose to hypoglycemic episodes. (2) The thrifty genotype theory, which holds that energy expenditure is efficient so as to maximize energy stores, predicts that these adaptations may enhance survival in periods of famine but predispose to obesity in modern dietary environments.
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal H3T 1C5, QC, Canada.
authors.forename: Shu Pei
authors.initials: SP
authors.lastname: Wang
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal H3T 1C5, QC, Canada; Laboratory of Animal Fat Deposition and Muscle Development, College of Animal Science and Technology, Northwest A&F University, Yangling 712100, Shaanxi, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Yang
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal H3T 1C5, QC, Canada.
authors.forename: Jiang Wei
authors.initials: JW
authors.lastname: Wu
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal H3T 1C5, QC, Canada.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Gauthier
authors.affiliation: Department of Pediatrics, Gifu University School of Medicine, Gifu 500, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Fukao
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, Université de Montréal and CHU Sainte-Justine, 3175 Côte Sainte-Catherine, Montreal H3T 1C5, QC, Canada. Electronic address: grant.mitchell@recherche-ste-justine.qc.ca.
authors.forename: Grant A
authors.initials: GA
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D005075:Biological Evolution; D001921:Brain / Q000378:metabolism / Q000502:physiology; D006801:Humans; D007657:Ketone Bodies; D050356:Lipid Metabolism / Q000502:physiology*; D051379:Mice; D008928:Mitochondria / Q000502:physiology; D014280:Triglycerides
chemical_list: D007657:Ketone Bodies; D014280:Triglycerides
keywords: Brain evolution; Carnitine palmitoyl transferase; Fatty acids; Inuit; Ketone bodies; Thrifty genotype; Triglycerides