Abstract 13314: Omega-3 Fatty Acid Deficiency Reprograms Gene Networks in the Hypothalamus and Contributes to Metabolic Syndrome in Rat
Metabolic syndrome (MetS), a cluster of metabolic risk phenotypes including obesity, insulin resistance, hypertension, and dyslipidemia, contributes to the development of type 2 diabetes and cardiovascular diseases - the top leading causes of deaths in developed counties. We have embarked on studies to determine the effects of MetS on the brain and behavioral consequences. In our previous study, deficiency in dietary docosahexaenoic acid (DHA), one of the major omega-3 fatty acids in the brain, was found to induce peripheral metabolic disturbances such as increased triglyceride levels and reduced insulin sensitivity, as well as to compromise learning and memory abilities (Agrawal et al., J Physiolo 2012). In order to explore the molecular complexity underlying the effects of DHA on MetS, we profiled the transcriptome in the hypothalamus (master regulator of metabolic homeostasis) of rats fed with a DHA-deficient diet using high throughput RNA sequencing and compared with the transcriptome of rats on a DHA-sufficient diet. We observed large-scale transcriptomic changes (192 genes and 944 transcripts with differential expression, and 732 genes with alternative splicing, p <0.05 Student’s t test) in response to DHA deficiency. Pathway analysis suggested that these “hypothalamus signatures” of DNA deficiency were enriched for pathways related to neuron functions, immune functions, IGF signaling, protein metabolism, and extracellular matrix organization, indicating a broad perturbation of housekeeping functions of hypothalamus. Importantly, these rat hypothalamus signatures were significantly enriched for genetic risk signals uncovered from genome-wide association studies (GWAS) of metabolic diseases in humans, including type 2 diabetes, hypertension, and dyslipidemia (p < 2x 10 -3 as assessed by both Fisher’s exact test and Kolmogorov-Smirnov test). By integrating components of network biology, we derived a DHA deficiency-perturbed hypothalamus gene network that entails the interactions among the hypothalamus signatures, and identified key network regulators such as Islr, Bgn, and Serping1. In summary, our study provides the much needed systems-level insights into the molecular mechanisms by which DHA deficiency affects MetS.
- © 2013 by American Heart Association, Inc.