Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet

Sung-Eun Kim; Jinsil Choo; Joon Yoon; Jae Ryang Chu; Yun Jung Bae; Seungyeoun Lee; Taesung Park; Mi-Kyung Sung

doi:10.1371/journal.pone.0171664

Genome-wide analysis identifies colonic genes differentially associated with serum leptin and insulin concentrations in C57BL/6J mice fed a high-fat diet

PLoS One. 2017 Feb 7;12(2):e0171664. doi: 10.1371/journal.pone.0171664. eCollection 2017.

Authors

Sung-Eun Kim¹, Jinsil Choo², Joon Yoon³, Jae Ryang Chu², Yun Jung Bae⁴, Seungyeoun Lee⁵, Taesung Park^{3

6}, Mi-Kyung Sung¹

Affiliations

¹ Department of Food and Nutrition, Sookmyung Women's University, Seoul, Republic of Korea.
² Department of Life Systems, Sookmyung Women's University, Seoul, Republic of Korea.
³ Interdisciplinary Program in Bioinformatics, Seoul National University, Seoul, Republic of Korea.
⁴ Division of Food Science and Culinary Arts, Shinhan University, Gyeonggi-do, Republic of Korea.
⁵ Department of Mathematics and Statistics, Sejong University, Seoul, Republic of Korea.
⁶ Department of Statistics, Seoul National University, Seoul, Republic of Korea.

Abstract

Obesity-induced chronic inflammation is known to increase the risk of ulcerative colitis, Crohn's disease, and colorectal cancer. Accumulating evidence suggests that leptin and insulin are key molecules linking obesity with diseases of the lower intestine. Here, we identified serum phenotype-associated genes in the colon of diet-induced obese mice as early biomarkers of obesity-associated colonic diseases. C57BL/6J mice were fed with either normal diet (ND, 15% of fat calories) or high-fat diet (HFD, 45% of fat calories) for 8 weeks. Serum concentrations of insulin, insulin-like growth factor-1 (IGF-1), leptin, and adiponectin were measured as obesity-related phenotypic markers. Genome-wide gene expression profiles of colon tissue were determined, followed by statistical analyses to detect differentially expressed and serum phenotype-associated genes. HFD-fed mice showed higher serum concentrations of leptin (P < 0.001) and insulin (P < 0.01) than those in the ND group, whereas serum IGF-1 and adiponectin concentrations did not differ between the two dietary groups. Among differentially expressed genes affected by HFD, 135, 128, 110, and 341 genes were associated with serum levels of leptin, insulin, IGF-1, and adiponectin, respectively. We identified 17 leptin-associated genes and 4 insulin-associated genes that inversely responded to HFD and ND. Among these, leptin-associated Peli3 (Pellino E3 ubiquitin protein ligase family member 3), Creb1 (cAMP responsive element binding protein 1), and Enpp2 (ectonucleotide pyrophosphatase/phosphodiesterase 2, autotaxin) and insulin-associated Centg1 (AGAP2, ArfGAP with GTPase domain) are reported to play a role either in obesity or colonic diseases. mRNA expression of these genes was validated by RT-qPCR. Our data suggest Peli3, Creb1, Enpp2, and Centg1 as potential early biomarker candidates for obesity-induced pathophysiological changes in the colon. Future studies verifying the function of these candidates are needed for the prevention, early detection, and treatment of colon diseases.

MeSH terms

Animals
Biomarkers
Colon / metabolism
Computational Biology / methods
Diet, High-Fat*
Gene Expression Profiling
Genetic Association Studies*
Genome-Wide Association Study
Insulin / blood*
Leptin / blood*
Male
Mice
Mice, Inbred C57BL
Phenotype

Substances

Biomarkers
Insulin
Leptin

Grants and funding

This research was supported by the SRC program (Center for Food & Nutritional Genomics: No.2015R1A5A6001906) and the Mid-Career Research Program (No.2015R1A2A2A01004607) of the National Research Foundation of Korea (NRF, www.nrf.re.kr/nrf_eng_cms/) funded by the Ministry of Education, Science and Technology to M-KS. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.