A MicroRNA Linking Human Positive Selection and Metabolic Disorders

Lifeng Wang; Nasa Sinnott-Armstrong; Alexandre Wagschal; Abigail R Wark; Joao-Paulo Camporez; Rachel J Perry; Fei Ji; Yoojin Sohn; Justin Oh; Su Wu; Jessica Chery; Bahareh Nemati Moud; Alham Saadat; Simon N Dankel; Gunnar Mellgren; Divya Sri Priyanka Tallapragada; Sophie Madlen Strobel; Mi-Jeong Lee; Ryan Tewhey; Pardis C Sabeti; Anne Schaefer; Andreas Petri; Sakari Kauppinen; Raymond T Chung; Alexander Soukas; Joseph Avruch; Susan K Fried; Hans Hauner; Ruslan I Sadreyev; Gerald I Shulman; Melina Claussnitzer; Anders M Näär

doi:10.1016/j.cell.2020.09.017

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.

Authors

Lifeng Wang¹, Nasa Sinnott-Armstrong², Alexandre Wagschal¹, Abigail R Wark³, Joao-Paulo Camporez⁴, Rachel J Perry⁴, Fei Ji⁵, Yoojin Sohn¹, Justin Oh¹, Su Wu¹, Jessica Chery¹, Bahareh Nemati Moud⁶, Alham Saadat⁷, Simon N Dankel⁸, Gunnar Mellgren⁸, Divya Sri Priyanka Tallapragada⁸, Sophie Madlen Strobel⁹, Mi-Jeong Lee¹⁰, Ryan Tewhey¹¹, Pardis C Sabeti¹², Anne Schaefer¹³, Andreas Petri¹⁴, Sakari Kauppinen¹⁴, Raymond T Chung¹⁵, Alexander Soukas¹⁶, Joseph Avruch¹⁷, Susan K Fried¹⁰, Hans Hauner¹⁸, Ruslan I Sadreyev⁵, Gerald I Shulman⁴, Melina Claussnitzer¹⁹, Anders M Näär²⁰

Affiliations

¹ Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Genetics, Stanford University School of Medicine, Stanford, CA 94305, USA.
³ Department of Genetics, Harvard Medical School, Boston, MA 02115, USA.
⁴ Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, New Haven, CT 06510, USA.
⁵ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
⁶ Else Kroener-Fresenius-Center of Nutritional Medicine, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany.
⁷ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁸ Mohn Nutrition Research Laboratory, Department of Clinical Science, University of Bergen, 5021 Bergen, Norway; Hormone Laboratory, Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, 5020 Bergen, Norway.
⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute of Nutritional Medicine, School of Medicine, Technical University of Munich, 80992 Munich, Germany.
¹⁰ Obesity Center, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
¹¹ Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
¹² Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA.
¹³ Fishberg Department of Neuroscience and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
¹⁴ Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, 2450 Copenhagen, Denmark.
¹⁵ Liver Center, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
¹⁶ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Medicine, Center for Genomic Medicine and Diabetes Unit, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA.
¹⁷ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA; Department of Medicine, Harvard Medical School, Boston, MA 02114, USA; Diabetes unit, Medical Services, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁸ Else Kroener-Fresenius-Center of Nutritional Medicine, School of Life Sciences, Technical University of Munich, 85354 Freising, Germany; Institute of Nutritional Medicine, School of Medicine, Technical University of Munich, 80992 Munich, Germany.
¹⁹ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
²⁰ Massachusetts General Hospital Cancer Center, Charlestown, MA 02129, USA; Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: naar@berkeley.edu.

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

Abstract

Publication types

MeSH terms

Substances

Grants and funding