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Principal Investigator: Aaron Clifford Brown
Organization: MAINEHEALTH
Fiscal Year: 2021
Award: $430,000
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <Ablation><Abscission><Address><Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Alleles><Allelomorphs><Apoplexy><Assay><Autophagocytosis><Autoregulation><Basal Transcription Factor><Basal transcription factor genes><Bioassay><Biogenesis><Biologic Assays><Biological Assay><Body Temperature><Body Tissues><Body Weight decreased><Brain Vascular Accident><Burn injury><Burns><CRISPR><CRISPR/Cas system><Cardiac Diseases><Cardiac Disorders><Cardiovascular Diseases><Cell Body><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Clustered Regularly Interspaced Short Palindromic Repeats><Data><Diet><Disease><Disorder><Economic Burden><Electron Transport><Energy Expenditure><Energy Metabolism><Equilibrium><Excision><Extirpation><Fat Cells><Fats><Fatty Tissue><Fatty acid glycerol esters><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genus Hippocampus><Goals><Health Care Systems><Healthcare Systems><Heart Diseases><Heat Production><High Fat Diet><Homeostasis><Human><Hypertrophy><Impairment><In Vitro><Inflammation><Intermediary Metabolism><Intervention><Intervention Strategies><Ketosis-Resistant Diabetes Mellitus><Knock-out><Knockout><Link><Lipids><Lipocytes><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Measures><Mediating><Metabolic><Metabolic Processes><Metabolic dysfunction><Metabolism><Mice><Mice Mammals><Micro RNA><MicroRNAs><Mitochondria><Mitochondrial Proteins><Modeling><Modern Man><Molecular><Murine><Mus><Mutant Strains Mice><NIDDM><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Obesity><Obesity Epidemic><Obesity associated disease><Obesity related disease><Origin of Life><Pathway interactions><Phenocopy><Phenotype><Physiological Homeostasis><Polyribosomes><Polysomes><Process><Production><Progenitor Cells><Public Health><Regulation><Removal><Reporter><Research><Resistance><Respiration><Rewarming><Risk><Role><Seahorse><Slow-Onset Diabetes Mellitus><Stable Diabetes Mellitus><Stimulus><Stroke><Surgical Removal><System><T2 DM><T2D><T2DM><Technology><Temperature><Testing><Therapeutic><Thermogenesis><Tissues><Transcription Factor Proto-Oncogene><Transcription factor genes><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Up-Regulation><Upregulation><Weight Gain><Weight Increase><Weight Loss><Weight Reduction><Weight maintenance regimen><adipocyte development><adipocyte differentiation><adipogenesis><adipose><adiposity><adult onset diabetes><autophagy><balance><balance function><blood glucose regulation><body weight gain><body weight increase><body weight loss><brain attack><burned><cardiovascular disorder><cerebral vascular accident><cerebrovascular accident><co-morbid><co-morbidity><comorbidity><corpulence><cost><develop therapy><diet-associated obesity><diet-induced obesity><diet-related obesity><diets><dosage><electron transfer><energy balance><exosome><fighting><glucose control><glucose homeostasis><glucose regulation><heart disorder><iPS><iPSC><iPSCs><improved><in vivo><induced pluripotent stem cell><inhibitor><inhibitor/antagonist><intervention development><interventional strategy><ketosis resistant diabetes><lipid biosynthesis><lipogenesis><maturity onset diabetes><miRNA><miRNAs><mitochondrial><mouse model><mouse mutant><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><new drug treatments><new drugs><new therapeutics><new therapy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel therapeutics><novel therapy><obesity development><overexpress><overexpression><paralog><paralogous gene><pathway><resection><resistant><respiratory mechanism><response><social role><stem cell differentiation><stem cells><therapy development><tool><transcription factor><treatment development><type 2 DM><type II DM><type two diabetes><weight control><weight management><white adipose tissue><wt gain><wt-loss><yellow adipose tissue>