A MicroRNA Linking Human Positive Selection and Metabolic Disorders

Cell. 2020 Oct 29;183(3):684-701.e14. doi: 10.1016/j.cell.2020.09.017. Epub 2020 Oct 14.

Abstract

Positive selection in Europeans at the 2q21.3 locus harboring the lactase gene has been attributed to selection for the ability of adults to digest milk to survive famine in ancient times. However, the 2q21.3 locus is also associated with obesity and type 2 diabetes in humans, raising the possibility that additional genetic elements in the locus may have contributed to evolutionary adaptation to famine by promoting energy storage, but which now confer susceptibility to metabolic diseases. We show here that the miR-128-1 microRNA, located at the center of the positively selected locus, represents a crucial metabolic regulator in mammals. Antisense targeting and genetic ablation of miR-128-1 in mouse metabolic disease models result in increased energy expenditure and amelioration of high-fat-diet-induced obesity and markedly improved glucose tolerance. A thrifty phenotype connected to miR-128-1-dependent energy storage may link ancient adaptation to famine and modern metabolic maladaptation associated with nutritional overabundance.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adipocytes, Brown / pathology
  • Adiposity
  • Alleles
  • Animals
  • Cell Differentiation
  • Cell Line
  • Cells, Cultured
  • Diet, High-Fat
  • Energy Metabolism
  • Epigenesis, Genetic
  • Genetic Loci
  • Glucose / metabolism
  • Homeostasis
  • Humans
  • Hypertrophy
  • Insulin Resistance
  • Leptin / deficiency
  • Leptin / metabolism
  • Male
  • Mammals / genetics
  • Metabolic Diseases / genetics*
  • Mice, Inbred C57BL
  • Mice, Obese
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Obesity / genetics
  • Oligonucleotides / metabolism
  • Species Specificity

Substances

  • Leptin
  • MIRN128 microRNA, human
  • MicroRNAs
  • Oligonucleotides
  • Glucose