The gut microbiota as an environmental factor that regulates fat storage

doi:10.1073/pnas.0407076101

The gut microbiota as an environmental factor that regulates fat storage

^*Center for Genome Sciences and Departments of ^†Molecular Biology and Pharmacology, ^∥Genetics, and ^§§Medicine, Cell Biology, and Physiology, Washington University School of Medicine, St. Louis, MO 63110; ^§Samuel Luenfeld Research Institute, Mount Sinai Hospital, Toronto, ON, Canada M5G 1X5; ^††Biomedical Center, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, Republic of Korea; and ^‡‡Department of Medical Genetics and Microbiology, University of Toronto, Toronto, ON, Canada M5S 1A8

Contributed by Jeffrey I. Gordon September 24, 2004

Abstract

New therapeutic targets for noncognitive reductions in energy intake, absorption, or storage are crucial given the worldwide epidemic of obesity. The gut microbial community (microbiota) is essential for processing dietary polysaccharides. We found that conventionalization of adult germ-free (GF) C57BL/6 mice with a normal microbiota harvested from the distal intestine (cecum) of conventionally raised animals produces a 60% increase in body fat content and insulin resistance within 14 days despite reduced food intake. Studies of GF and conventionalized mice revealed that the microbiota promotes absorption of monosaccharides from the gut lumen, with resulting induction of de novo hepatic lipogenesis. Fasting-induced adipocyte factor (Fiaf), a member of the angiopoietin-like family of proteins, is selectively suppressed in the intestinal epithelium of normal mice by conventionalization. Analysis of GF and conventionalized, normal and Fiaf knockout mice established that Fiaf is a circulating lipoprotein lipase inhibitor and that its suppression is essential for the microbiota-induced deposition of triglycerides in adipocytes. Studies of Rag1-/- animals indicate that these host responses do not require mature lymphocytes. Our findings suggest that the gut microbiota is an important environmental factor that affects energy harvest from the diet and energy storage in the host.

Footnotes

↵ ¶¶ To whom correspondence should be addressed. E-mail: jgordon{at}molecool.wustl.edu.
↵ ‡ F.B. and H.D. contributed equally to this work.
↵ ¶ Present address: Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada R3E OW3.
↵ ** Present address: Center for Immunology, University of Texas Southwestern Medical Center, Dallas, TX 75390.
Author contributions: F.B., C.F.S., and J.I.G. designed research; F.B., H.D., and L.V.H. performed research; F.B., H.D., G.Y.K., and A.N. contributed new reagents/analytic tools; F.B., T.W., A.N., C.F.S., and J.I.G. analyzed data; F.B. and J.I.G. wrote the paper.
Abbreviations: GF, germ-free; Fiaf, fasting-induced adipocyte factor; B6, C57BL/6J; PPAR, peroxisome proliferator-activator receptor; CONV-R, conventionally raised; CONV-D, conventionalized; qRT-PCR, quantitative RT-PCR; LPL, lipoprotein lipase; Acc1, acetyl-CoA carboxylase; Fas, fatty acid synthase; SREBP-1, sterol response element binding protein 1; ChREBP, carbohydrate response element binding protein.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AY667702-AY668946).
Freely available online through the PNAS open access option.