KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

Proc Natl Acad Sci U S A. 2016 Dec 13;113(50):14372-14377. doi: 10.1073/pnas.1611243113. Epub 2016 Nov 28.

Abstract

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Keywords: FGF21; alcohol consumption; human; mouse model; β-Klotho.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alcohol Drinking / genetics*
  • Alcohol Drinking / physiopathology*
  • Animals
  • Behavior, Animal / physiology
  • Brain / physiopathology
  • Emotions / physiology
  • Female
  • Fibroblast Growth Factors / physiology*
  • Genome-Wide Association Study
  • Humans
  • Liver / physiopathology
  • Male
  • Membrane Proteins / deficiency
  • Membrane Proteins / genetics*
  • Membrane Proteins / physiology
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polymorphism, Single Nucleotide

Substances

  • KLB protein, human
  • Klb protein, mouse
  • Membrane Proteins
  • fibroblast growth factor 21
  • Fibroblast Growth Factors