Lipocalin 2 deficiency-induced gut microbiota dysbiosis evokes metabolic syndrome in aged mice

Physiol Genomics. 2020 Aug 1;52(8):314-321. doi: 10.1152/physiolgenomics.00118.2019. Epub 2020 Jul 6.


Lipocalin 2 (Lcn2) is a multifunctional innate immune protein that limits microbial overgrowth. Our previous study demonstrated that the gut microbiota directly induces intestinal Lcn2 production, and Lcn2-deficient (Lcn2-/-) mice exhibit gut dysbiosis. Coincidentally, gut dysbiosis is associated with metabolic syndrome pathogenesis, and elevated Lcn2 levels has been considered a potential clinical biomarker of metabolic syndrome. Yet whether Lcn2 mitigates or exacerbates metabolic syndrome remains inconclusive. Our objective was to determine whether Lcn2 deficiency-induced compositional changes in gut microbiota contribute to gain in adiposity in aged mice. Utilizing Lcn2-/- mice and their wild-type (WT) littermates, we measured metabolic markers, including fasting blood glucose, serum lipids, fat pad weight, and insulin resistance at ages 3, 6, and 9 mo old. Relative to WT mice, aged Lcn2-/- mice exhibited a gain in adiposity associated with numerous features of metabolic syndrome, including insulin resistance and dyslipidemia. Surprisingly, supplementation with a high-fat diet did not further aggravate metabolic syndrome that spontaneously occurs in Lcn2-/- mice by 6 mo of age. Interestingly, chow-fed Lcn2-/- mice displayed marked differences in the bacterial abundance and metabolomic profile of the gut microbiota compared with WT mice. Overall, our results demonstrate that Lcn2 is essential to maintain metabolic and gut microbiotal homeostasis, where deficiency induces spontaneous delayed onset of metabolic syndrome.

Keywords: dyslipidemias; insulin resistance; microbial-host interactions; obesity.

Publication types

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

MeSH terms

  • Adipose Tissue
  • Adiposity / genetics
  • Aging / metabolism*
  • Animals
  • Blood Glucose / analysis
  • Diet, High-Fat
  • Disease Models, Animal
  • Dysbiosis / blood
  • Dysbiosis / complications*
  • Dysbiosis / metabolism*
  • Dysbiosis / microbiology
  • Dyslipidemias / blood
  • Dyslipidemias / complications*
  • Dyslipidemias / microbiology
  • Female
  • Gastrointestinal Microbiome / genetics*
  • Gastrointestinal Microbiome / immunology
  • Homeostasis / genetics
  • Lipocalin-2 / deficiency*
  • Lipocalin-2 / genetics
  • Male
  • Metabolic Syndrome / blood
  • Metabolic Syndrome / complications*
  • Metabolic Syndrome / metabolism*
  • Metabolic Syndrome / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Obesity / metabolism


  • Blood Glucose
  • Lipocalin-2
  • Lcn2 protein, mouse