Lessons from “Lower” Organisms: What Worms, Flies, and Zebrafish Can Teach Us about Human Energy Metabolism

and zebrafish can teach us about human energy metabolism. PLoS Genet 3(11): e199. doi:10.1371/journal.pgen.0030199 Lessons from ''Lower'' Organisms: What Worms, Flies, and Zebrafish Can Teach Us about Human Energy Metabolism Amnon Schlegel 0 Didier Y. R. Stainier 0 0 Amnon Schlegel is with the Department of Biochemistry and Biophysics and the Department of Medicine, Division of Endocrinology at the University of California San Francisco , in San Francisco , California, United States of America. Didier Y. R. Stainier is with the Department of Biochemistry and Biophysics, Programs in Developmental Biology, Genetics and Human Genetics, the Cardiovascular Research Institute, Diabetes Center, Cancer Center, and Liver Center at the University of California San Francisco , in San Francisco, California , United States of America A diabetes mellitus, and obesity), unleashed by multiple pandemic of metabolic diseases (atherosclerosis, social and economic factors beyond the control of most individuals, threatens to diminish human life span for the first time in the modern era. Given the redundancy and inherent complexity of processes regulating the uptake, transport, catabolism, and synthesis of nutrients, magic bullets to target these diseases will be hard to find. Recent studies using the worm Caenorhabditis elegans, the fly Drosophila melanogaster, and the zebrafish Danio rerio indicate that these ''lower'' metazoans possess unique attributes that should help in identifying, investigating, and even validating new pharmaceutical targets for these diseases. We summarize findings in these organisms that shed light on highly conserved pathways of energy homeostasis. - Major shifts in human populations to urban centers, engagement in sedentary employment and leisure activities, and over-abundance of calorie-dense, processed foods have created a milieu in which ancient metabolic pathways that evolved under pressures to extract enough energy from the environment to maintain optimal reproductive and immune function and to tolerate short bouts of fasting, while avoiding excessive weight gain that would hinder escape from wouldbe predators, are running amuck [1]. The consequence of excess stored energy, human obesity, is poised to negate the tremendous improvements in sanitation, obstetric care, and massive vaccination that marked the developed world in the last century. For the first time in the modern era, life expectancy is expected to decrease [2]. Recognizing that it is unlikely that the social and economic pressures that generated our toxic lifestyle will be reversed, current research in energy metabolism focuses on mitigating the consequences of modernity. Increasingly sophisticated approaches are required to understand the critical nodes of energy homeostasis and to develop new drug targets. The energy-producing, storing, and transferring reactions of life are a common thermodynamic inheritance of all organisms. The large catalog of in-born errors in human metabolism includes a series of mutations ranging in phenotype from mildly hypomorphic (e.g., 75% loss in activity) to completely null (e.g., absence of activity) in the key enzymes of cellular energetics that are shared by metazoans (Figure 1). Although these mutations are rare in the general population, elucidation of the genetic and biochemical underpinnings of monoallelic diseases has greatly helped focus research in more common diseases, in general [3], and of energy metabolism, in particular. Several such disorders have comparable syndromes in lower metazoans (Table 1). As will be discussed below, unbiased methods have been used to identify more genes whose mutation in lower metazoans leads to phenotypes that are comparable to human syndromes of altered energy homeostasis like obesity. Since it is unlikely that the social and economic pressures that have generated a global pandemic of obesity will be reversed, creative tools are required to understand the signaling pathways that govern energy homeostasis and to develop new drug targets that exploit this new knowledge. In this review, we highlight metabolic research in three metazoan organisms, and argue that these studies are not mere exercises in comparative energetics (Table 2). Rather, studies on energy homeostasis in C. elegans, Drosophila, and zebrafish are proving that genetically tractable lower organisms can alter our understanding of the relationship of metabolic processes underlying obesity and its related illnesses (atherosclerotic vascular disease and type 2 diabetes mellitus). Through study of these organisms, insights relating energy homeostasis to life span, reproduction, and immune function have been made [47]. Below we focus on studies of neutral lipid homeostasis in these organisms because lipids are the main energy storage material and drug targets to combat obesity will necessarily alter their metabolism. Insulin/Insulin-Like Growth Factor Signaling, Bridging Metabolic Control and Regulation of Life Span, Reproduction, and Immune Function The evolutionarily central insulin/insulin-like growth factor signaling pathway (IIS) has been characterized in great detail in Drosophila and C. elegans. Orthologous proteins for nearly all of the intermediates in this cascade are found in vertebrates. Multiple mutations in components of the IIS pathway result in alterations in life span [8], have differential effects on body size and fertility, and cause alterations in fat accumulation in their major lipid storage organs [47]. A consensus is emerging, however, that decreased adiposity, achieved through genetic lesions in IIS in lower metazoan, dietary restriction in rodents, and bariatric surgery in humans, can prolong healthy life span [911]. C. elegans, Studying Whole-Organism Lipid Stores One Gut Granule at a Time In C. elegans adults, triacylglycerol (TAG) is stored in gut granules (Figure 2), enterocyte lysosomes, whose genesis, size, and traffic are amenable to genetic study [1215]. These structures are not directly analogous to the lipid droplets seen in the Drosophila fat body, or in vertebrate adipose tissue; however, gut granule form and function is regulated by highly conserved nutrient sensing and intracellular signaling Four novel genes were identified in a genetic screen for mutations causing gut granule loss (glo mutants) by searching for defects in the accumulation of fluorescent dyes that label acidified, mature lysosomes specifically [13]. 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