Lymphotoxin regulates commensal responses to enable diet-induced obesity

Nat Immunol. 2012 Oct;13(10):947-53. doi: 10.1038/ni.2403. Epub 2012 Aug 26.

Abstract

Microbiota are essential for weight gain in mouse models of diet-induced obesity (DIO), but the pathways that cause the microbiota to induce weight gain are unknown. We report that mice deficient in lymphotoxin, a key molecule in gut immunity, were resistant to DIO. Ltbr(-/-) mice had different microbial community composition compared to their heterozygous littermates, including an overgrowth of segmented filamentous bacteria (SFB). Furthermore, cecal transplantation conferred leanness to germ-free recipients. Housing Ltbr(-/-) mice with their obese siblings rescued weight gain in Ltbr(-/-) mice, demonstrating the communicability of the obese phenotype. Ltbr(-/-) mice lacked interleukin 23 (IL-23) and IL-22, which can regulate SFB. Mice deficient in these pathways also resisted DIO, demonstrating that intact mucosal immunity guides diet-induced changes to the microbiota to enable obesity.

Publication types

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

MeSH terms

  • Animals
  • Bacteria / growth & development
  • Bacteria / immunology
  • Cecum / microbiology
  • Cecum / transplantation
  • Diet
  • Energy Metabolism
  • Germ-Free Life
  • Immunity, Mucosal*
  • Interleukin-23 / deficiency
  • Interleukin-23 / physiology
  • Interleukins / deficiency
  • Interleukins / physiology
  • Lymphotoxin beta Receptor / genetics
  • Lymphotoxin beta Receptor / physiology*
  • Lymphotoxin-alpha / deficiency
  • Lymphotoxin-alpha / genetics
  • Lymphotoxin-alpha / physiology*
  • Metagenome
  • Mice
  • Mice, Knockout
  • Obesity* / etiology
  • Obesity* / immunology
  • Obesity* / metabolism
  • Weight Gain / immunology

Substances

  • Interleukin-23
  • Interleukins
  • Ltbr protein, mouse
  • Lymphotoxin beta Receptor
  • Lymphotoxin-alpha
  • interleukin-22