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DiaComp Funded Abstracts

Program Application Abstract
A “Thrifty” MicroRNA: an Evolutionary Explanation for a Non-­Coding RNA Implicated in Metabolic Disorders
Bennett, Dylan   (Massachusetts General Hospital)
Around 40,000 years ago Homo sapiens began to migrate into the European continent in large numbers for the first time. They were faced with an unpredictable, and sometimes harsh environment as well as the great irregularity of food availability that came with living in the temperate climate as hunters/gatherers. With the advent of agriculture 5-­10,000 years ago, greatly increased food availability led to a substantial population expansion, however cycles of feast and famine placed great evolutionary selective pressures upon traits advantageous to the acquisition and storage of energy. In addition, migration to higher latitudes necessitated increased fat storage to survive the long, cold winters. This evolutionary environment provides the basis for the genetic selection for traits promoting energy storage during times of high food availability to survive famine. However, in the the current developed world with constant food availability, this “thrifty” trait has become a liability, resulting in a dramatic rise in metabolic disorders such as obesity, type 2 diabetes, non-­alcoholic fatty liver diseases, and cardiovascular disease. While most studies to date have focused on genes in the etiology of metabolic diseases, we have recently identified a microRNA as a master regulator of metabolic homeostasis. MicroRNAs are short (20-­24 nucleotides) regulatory non-­coding RNAs that control mRNA translation and expression. A number of microRNAs have been shown to represent crucial modulators of mammalian physiology, development, and disease. Our studies uncovered a “thrifty” microRNA located in a genomic locus that has been shown to be under strong positive selection in recent human evolution, and that is genetically linked to obesity, type 2 diabetes, and cholesterol/lipid abnormalities in European populations. Importantly, antisense ablation and genetic KO of this ‘’thrifty” microRNA in mouse high fat diet-­induced obesity models result in profound beneficial effects on whole animal metabolism, such as a strong decrease in body weight and fat mass, improved glucose homeostasis, decreased hepatic steatosis, adipose hypertrophy, and inflammation, and lowered total cholesterol and triglycerides. Our studies reveal that the “thrifty” microRNA acts at least in part by switching whole body energy metabolism from a state of energy expenditure to a state of energy storage. We also demonstrate here a link between the microRNA expression and common genetic variants (single nucleotide polymorphisms;; SNPs) associated with positive selection and metabolic disorders through quantification of the microRNA in human adipose tissue samples. These links suggest that the microRNA performs a similar role in humans to that found in our mouse models. Taken together, our data suggest that the microRNA indeed plays a crucial "thrifty” role by negatively regulating expression of energy expenditure genes. We posit that evolutionary pressures have selected for elevated microRNA expression in Northern European populations to better conserve energy under the selective pressures of a “feast or famine” environment and that in the absence of such pressures in modern society, expression may contribute to the onset of the metabolic diseases that have become so pervasive today.