PhD project in MicroRNA-dependent control of healthy metabolism by brown adipocytes

Overview

Brown adipose tissue (BAT) is specialised type of fat with unique properties that determine its important role in healthy metabolism and protection from obesity. In recent years, there has been a renaissance in BAT research following its detection in adult humans and potential benefits to health. This project will investigate the role of microRNAs in brown adipocyte gene expression, differentiation and bioenergetics.

Brown fat is extremely rich in mitochondria which through the action of BAT-specific factors function to generate heat. Thus, BAT contributes to total energy expenditure by burning fat for heat generation by thermogenesis and when maximally activated produces 300 times more heat per unit mass than any other organ in the body.

White adipose tissue (WAT) performs a contrasting function to BAT by serving as a storage site for triglycerides and excessive amounts negatively impacts health. However, following cold exposure or hormonal treatment a second type of brown adipocyte known as ‘brown-in-white’ or BRITE adipocyte is induced within WAT. Therefore, identification of new targets and pathways that increase BAT activity or promote BRITE adipocytes can be used to reduce obesity.

BAT expresses a set of unique genes required for its function. A growing body of evidence supports that microRNAs serve important roles in the control of gene expression in both brown and white adipocytes. MicroRNAs interact with mRNAs of target genes to suppress gene expression. The Christian group has identified a set of microRNAs that are enriched in brown compared to white adipocytes and determined that some have profound effects on the process of adipogenesis and expression of brown fat genes.

The research project will investigate the role of selected microRNAs as key regulators of the brown adipocyte programme. This PhD project aims to establish: (i) The role of microRNAs in brown adipocyte function, expression of key brown/BRITE adipocyte markers and mitochondrial function (ii) the role of microRNAs in the commitment of pluripotent stem cells and adipocyte precursors to brown/BRITE adipocytes and (iii) identification and validation of mRNA target genes of microRNAs in adipocytes.

During this project, the student will undergo skills training in a range of molecular biology techniques, cellular metabolism analysis, and bioinformatics. CRISPR-Cas9 gene editing or siRNA will be used to knockout microRNA expression in pre-adipocyte cell lines and mouse embryonic stem cells. Following their differentiation into brown adipocytes the role microRNA or target gene plays in expression of the brown fat programme will be determined by RT-qPCR of key BAT genes (e.g, UCP1, CIDEA). In addition, metabolic changes such as in mitochondrial capacity, rates of glycolysis and oxidative phosphorylation, will be assessed using Seahorse XF analyser.

Supervisor

• Prof Mark Christian
• mark.christian@ntu.ac.uk
• Tel: +44 (0)115 8483318