Submission
| Title: | The Microbiome Affects Host Metabolic Homeostasis via Differential Regulation of Gene Expression in the Neuroendocrine System |
| Co-Authors: |
Milhouse, Wynne, Stark Neurosciences Research Institute, Center for Diabetes and Metabolic Disease, Department of Pediatrics, Indiana University School of Medicine; Thian Hnem, Indiana University School of Medicine; Anna Clapp, Department of Nutrition Science, Purdue University; Tzu-Wen Cross, Department of Nutrition Science, Purdue University; Shijun Yan, Center for Diabetes and Metabolic Disease, Department of Pediatrics, Indiana University School of Medicine; Jason Conley, Center for Diabetes and Metabolic Disease, Department of Pediatrics, Indiana University School of Medicine; Hongxia Ren, Stark Neurosciences Research Institute, Center for Diabetes and Metabolic Disease, Department of Pediatrics, Indiana University School of Medicine |
Abstract
Background/Significance/Rationale: Genetic mutations in the endocrine system have been associated with metabolic disorders, though their severity may vary based on environmental modulating factors. The microbiome is one example of an understudied modulating factor with pleiotropic effects on human physiology. Consequentially, the role of microbiota in diet-induced obesity has been controversial. To address this question, we used germ-free and conventional mouse models to examine the expression of genes critical for neuroendocrine regulation of metabolic homeostasis.
Methods: Samples of the mediobasal hypothalamus (MBH) were obtained from 18 germ-free and 18 conventional C57BL/6 mice (n=9 males, 9 females). Each gene transcript was quantified using quantitative real-time polymerase chain reaction (qRT-PCR).
Results/Findings: Interestingly, our results showed that germ-free mice had increased expression of neuropeptides associated with feeding regulation, i.e.,Neuropeptide Y (p<f,m<0.0001) and Proopiomelanocortin (pf,m<0.0001), compared to conventional mice. Furthermore, conventional mice had increased expression of a negative regulator of leptin signaling, Suppressor of cytokine signaling 3 (pf<0.0108, pm<0.0001). For G-protein-coupled-receptor 162 (Gpr162), a gene believed to be involved in hedonic feeding, male conventional mice had a higher expression than germ-free males (pm<0.0032).
Conclusions/Discussion: Proopiomelanocortin (Pomc) and decreased expression of Suppressor of cytokine signaling 3 (Socs3) in germ-free mice compared to conventional mice, we believe this may contribute to the lean phenotype and protection from diet-induced obesity often observed in germ-free mice. Thus, the microbiome may impinge upon diverse effectors of the neuroendocrine system to regulate host metabolism. For future studies, we will continue investigating how the microbiome impacts host metabolism through gene transcription profiling in intestinal tissues.
Translational/Human Health Impact: A deeper understanding of how the microbiome contributes to disease pathophysiology could improve our comprehension of the modulating factors of rare diseases. Thus, in this study, we used precisely controlled animal models to illuminate key endocrine pathways connecting microbiota and human metabolism.
