Human Pluripotent Stem Cell-Derived Brown/Beige Adipocyte Models: Investigating Thermogenic Adipocyte Development and Function (360G-Wellcome-109153_Z_15_A)

Brown adipose tissue (BAT) is responsible for non-shivering thermogenesis and controls energy balance. With the discovery that human adults have functional BAT, the activity of which correlates with decreased BMI and increased energy expenditure, the ability to target BAT through increasing i) BAT mass, ii) BAT activity, or iii) white adipose tissue (WAT) browning, has emerged as a potential therapeutic approach for the treatment of obesity and related disorders. The study of thermogenic adipocytes is limited due to scarce tissue volume; we instead propose to use a chemically defined protocol for the generation of human pluripotent stem cell (hPSC)-derived thermogenic adipocytes. Using this model, brown adipocyte (BA) development and maturation will be assessed through analysis of gene/protein expression, cell morphology, and functional studies. Whole transcriptome analysis will be employed to identify candidate genes important for BA development and WAT browning. Candidate genes with roles in BA development and/or function identified through previous studies (e.g. LR11, BMP8B and GREMLIN1) will also be investigated. Using CRISPR/Cas9 genome editing techniques, hPSC lines with gain/loss of function of selected candidate genes will be generated and extensively phenotyped; the most promising gene will subsequently be investigated through the generation of mouse models.