Molecular Basis of Obesity and Obesity-induced Metabolic Diseases

National Heart, Lung, And Blood Institute

Investigators

Linked publications & trials

Abstract

The current obesity epidemic in the US is the major contributor to the soaring rates of metabolic diseases and to skyrocketing health care costs. Yet the molecular and pathological mechanisms by which obesity induces metabolic disorders remain incompletely understood, and therapeutic interventions for obesity and related metabolic abnormalities are limited. In recent years, tens of thousands of long non-coding RNAs lncRNAs (lncRNAs) have been identified to constitute a significant portion of the human genome and play a diverse role in biological processes. However, majority of human lncRNAs are human- or primate-specific and their relevance to diseases cannot be directly studied in any of the existing experimental systems. To systemically analyze the role of lncRNAs in human disease, we have identified liver-enriched human lncRNAs that are regulated by GWAS loci of major metabolic diseases or exhibit altered expression in patients with metabolic disorders. We also confirmed the in vivo role of several hepatocyte-enriched lncRNAs in lipid metabolism using a humanized mouse model in which the liver is populated with human hepatocytes. Our work thus supports that human lncRNAs can function as critical metabolic regulators and may play a role in the pathogenesis of metabolic diseases. The liver is composed of multiple cell types and the development of liver diseases often involves intertwined interplay amongst hepatocytes, stellate cells and immune cells. Encouraged by our findings on hepatocyte-specific lncRNAs, we are developing additional models to study the function of human lncRNAs enriched in all relevant cells of the liver.