The current epidemic of obesity and associated health problems is presenting significant public health challenges. The identification of new therapeutic strategies for regulating energy intake, absorption, and storage is therefore an important goal. The complex community of microorganisms residing within the digestive tract (microbiota) has recently been identified as an important environmental factor that regulates host nutrient metabolism and energy storage. The presence of the gut microbiota leads to a significant increase in body fat, caused in part by microbial suppression of intestinal epithelial expression of Fasting-induced adipose factor (Fiaf/Angptl4;a circulating inhibitor of lipoprotein lipase). The microbial signals and host transcriptional regulatory mechanisms that control Fiaf expression in the intestine remain completely unknown. The long-term goal of my research program is to understand the molecular mechanisms underlying host-microbial interactions in the digestive tract. We have established a gnotobiotic zebrafish model and used it to reveal evolutionarily-conserved roles for the zebrafish microbiota on host nutrient metabolism, including intestinal epithelial suppression of the zebrafish Fiaf ortholog. The optical transparency of the developing zebrafish, as well as the amenability of the zebrafish to genetic screens, provide new opportunities for investigating the roles of the microbiota in host biology. The overall objective of this application is to exploit the advantages of the zebrafish model to identify bacterial and host factors that regulate Fiaf expression. The proposed research will address the central hypothesis that intestinal bacteria signal through host transcriptional regulatory mechanisms to suppress Fiaf and thereby alter host energy balance. The rationale underlying the proposed research is that the identification of bacterial and host mechanisms that control Fiaf synthesis will provide new targets for the manipulation of host energy storage.
In Specific Aim 1, we will use a bacterial genetic approach to identify bacterial genes required for suppression of Fiaf.
In Specific Aim 2, we will use zebrafish transgenesis and genetic tests to identify host transcriptional regulatory mechanisms that control Fiaf expression in the intestine. The results of this research are expected to contribute a new understanding of the bacterial genes and host transcriptional regulatory mechanisms that regulate intestinal expression of Fiaf. This contribution is significant because it is expected to vertically advance the field of host-microbial mutualism in the intestine, and lead to the development of new therapeutic strategies for regulating energy storage in humans.

Public Health Relevance

Fat storage is influenced by the complex community of microorganisms residing in the intestine. The goal of the proposed research is to understand how intestinal microorganisms signal to their host to regulate fat storage. This new knowledge could lead to novel therapeutic approaches for prevention and treatment of obesity and related diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK081426-05
Application #
8286310
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Karp, Robert W
Project Start
2008-07-01
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2012
Total Cost
$288,045
Indirect Cost
$92,025
Name
University of North Carolina Chapel Hill
Department
Physiology
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Camp, J Gray; Frank, Christopher L; Lickwar, Colin R et al. (2014) Microbiota modulate transcription in the intestinal epithelium without remodeling the accessible chromatin landscape. Genome Res 24:1504-16
Goldsmith, Jason R; Cocchiaro, Jordan L; Rawls, John F et al. (2013) Glafenine-induced intestinal injury in zebrafish is ameliorated by ýý-opioid signaling via enhancement of Atf6-dependent cellular stress responses. Dis Model Mech 6:146-59
Cocchiaro, Jordan L; Rawls, John F (2013) Microgavage of zebrafish larvae. J Vis Exp :e4434
Wong, Sandi; Waldrop, Thomas; Summerfelt, Steven et al. (2013) Aquacultured rainbow trout (Oncorhynchus mykiss) possess a large core intestinal microbiota that is resistant to variation in diet and rearing density. Appl Environ Microbiol 79:4974-84
Camp, J Gray; Jazwa, Amelia L; Trent, Chad M et al. (2012) Intronic cis-regulatory modules mediate tissue-specific and microbial control of angptl4/fiaf transcription. PLoS Genet 8:e1002585
Roeselers, Guus; Mittge, Erika K; Stephens, W Zac et al. (2011) Evidence for a core gut microbiota in the zebrafish. ISME J 5:1595-608
Minchin, James E N; Rawls, John F (2011) In vivo analysis of white adipose tissue in zebrafish. Methods Cell Biol 105:63-86
Kanther, Michelle; Sun, Xiaolun; Mühlbauer, Marcus et al. (2011) Microbial colonization induces dynamic temporal and spatial patterns of NF-?B activation in the zebrafish digestive tract. Gastroenterology 141:197-207
Kanther, Michelle; Rawls, John F (2010) Host-microbe interactions in the developing zebrafish. Curr Opin Immunol 22:10-9
Camp, J Gray; Kanther, Michelle; Semova, Ivana et al. (2009) Patterns and scales in gastrointestinal microbial ecology. Gastroenterology 136:1989-2002

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