miR-27 mediated regulation of mitochondrial function in thermogenic adipocytes

Project Summary/Abstract The obesity epidemic is a global public health issue, that leads to an increased risk for type 2 diabetes and cardiovascular disease. Hypertrophy, inflammation, and excess lipid accumulation in white adipocytes within fat tissue are hallmarks of obesity that contribute to metabolic dysfunction. Unlike white adipocytes, beige adipocytes are rich in mitochondria, and expend energy to generate heat (thermogenesis) in response to stimuli such as cold exposure. This activity is associated with resistance to diet-induced obesity, and thus activation and expansion of beige adipocytes can counteract the obesity phenotype. During beige adipocyte activation, optimal thermogenic function is maintained by balancing mitochondrial biogenesis with autophagy- mediated mitochondrial degradation (mitophagy), which is finely coordinated to maintain mitochondrial homeostasis. Using our newly developed model of beige adipocyte differentiation and activation from human iPS cells, we discovered that thermogenic activation of beige adipocytes occurs following enhanced secretion of exosomes containing a variety of microRNAs (miRs), including miR-27a/b. miR-27 homologs (miR-27a/b) are anti-thermogenic miRs that suppress genes involved in mitochondrial biogenesis (such as FOXJ3) and mitophagy (including MFF). miR-27a/b are down-regulated in beige adipocytes during thermogenic activation, consistent with their predicted role as inhibitors of mitochondrial activation, turnover, and biogenesis. This project tests several hypotheses related to mechanisms of beige adipocyte activation. We propose that the miR-27 suppresses adipocyte thermogenesis by targeting FOXJ3 and MFF and that loss of miR-27a/b and increase in FOXJ3/MFF-mediated pathways activate mitochondrial activity and thermogenesis. We also propose that in vivo genetic targeting of miR-27a/b will allow us to identify the in vivo role of these miRs in beige adipocyte activation, regulation of mitochondrial proteins, thermogenesis and resistance to obesity. These questions will be tested in two focused specific aims: Specific Aim 1. Identify the mechanism of miR-27 regulation of beige adipocyte mitochondrial function. Specific Aim 2. Determine the effect of miR-27 suppression on the response of beige adipose tissue to temperature challenge and high-fat diet. These studies are expected to identify novel molecular mechanisms that may provide a new platform to increase beige adipogenesis and reverse obesity-related disorders.