SBIR-STTR Award

The activation and recruitment of brown adipose tissue has become an exciting target in the fight against obesity and its related metabolic diseases. Brown adipose tissue differs from white adipose tissue in its critical ability to burn energy as heat through UCP-1 driven adaptive thermogenesis. Expression of mitochondrial UCP-1 uncouples oxidative phosphorylation, resulting in accelerated substrate oxidation but low ATP production. The resulting dissipation of energy is associated with plasma triglyceride clearance, a key factor in weight loss. The brown adipose depot has long been known to exist in rodents as well as in human infants. However, recent evidence has demonstrated the existence of active brown adipose tissue in human adults. These findings prompted a resurgence of research focusing on both the activation of brown adipose tissue and the "browning" of white adipose tissue, a phenomenon wherein UCP-1-mediated mitochondrial uncoupling is induced by stimuli. Studies using rodent models have demonstrated that brown fat activation or induction of browning can promote beneficial metabolic effects, and promising therapeutic targets have been identified. However, the therapeutic potential of these targets has not been confirmed due to the lack of a widely available human brown adipocyte model. Therefore, there is a pronounced need to validate existing therapeutic targets in the human system. ZenBio will address this need by providing both a primary and immortalized human brown adipocyte cell culture system to the research community and will utilize these tools to establish a screen to identify activators of human brown adipogenesis. The principal goal of this project is to generate and characterize a human adult brown adipocyte cell system. We will achieve this in a stepwise fashion, beginning with an initial feasibility study focused on human fetal brown adipocytes. Aim I will use functional and genomic analyses to generate a widely available fetal brown adipocyte model which will be used as a tool to establish the adult cell system. The fetal model will be developed first due to the comparative ease of detecting fetal brown adipose tissue and its ready availability through existing procurement agencies. The second aim is to generate and characterize an immortalized fetal brown adipocyte system for high throughput/high content screening. These cells will circumvent the limited material and lifespan of primary cells and allow for the development of a high throughput screening platform to identify novel targets of brown adipocyte activation. Phase I will be expanded in Phase II with the goal of characterizing and commercializing the human adult brown adipocyte system from donors of differing BMI, age, gender and diabetic state. These studies will generate both primary and immortalized human adult adipocyte cells which will be used to identify novel targets of brown adipocyte energy expenditure for the treatment of obesity.

Public Health Relevance Statement:


Public Health Relevance:
The worldwide prevalence of obesity and its related diseases is at epidemic proportions necessitating novel therapeutic approaches. The recent identification of human adult brown fat has led researchers to investigate new ways to increase this beneficial adipose tissue to deter obesity related diseases. We will generate human brown adipocyte systems that can be used to discover and validate novel therapeutic modalities.

Project Terms:
Address; adipocyte differentiation; Adipocytes; Adipose tissue; Adult; Affect; Age; Benchmarking; Biological Assay; Biological Markers; Biological Models; Biology; Body Weight decreased; Brown Fat; Burn injury; Cell Culture System; Cell Line; Cell model; Cells; Communities; Comorbidity; comparative; Data; demographics; Development; diabetic; Disease; Drug Targeting; Energy Metabolism; Epidemic; experience; fatty acid oxidation; Feasibility Studies; fetal; Fetal Tissues; fight against; functional genomics; Gender; Generations; Genetic; Goals; Heating; high throughput screening; Human; Human Identifications; immortalized cell; Incidence; Infant; Knowledge; Lead; lipid biosynthesis; Location; Longevity; Measures; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Modality; Modeling; Non-Insulin-Dependent Diabetes Mellitus; novel; novel therapeutic intervention; novel therapeutics; Obesity; Obesity associated disease; obesity treatment; oxidation; Oxidative Phosphorylation; Pathway interactions; Performance; Phase; phase 1 study; Plasma; Population; Prevalence; Procedures; Production; Protocols documentation; Provider; public health relevance; Quality Control; Research; Research Personnel; Respiration; Rodent; Rodent Model; screening; Stimulus; System; Targeted Research; Testing; Therapeutic; therapeutic target; Thermogenesis; Tissues; tool; Triglycerides; United States; Validation

The activation and recruitment of brown adipose tissue has become an exciting target in the fight against obesity and its related metabolic diseases. Brown adipose tissue differs from white adipose tissue in its critical ability to burn energy as heat through UCP-1 driven adaptive thermogenesis. Expression of mitochondrial UCP-1 uncouples oxidative phosphorylation, resulting in accelerated substrate oxidation but low ATP production. The resulting dissipation of energy is associated with plasma triglyceride clearance, a key factor in weight loss. The brown adipose depot has long been known to exist in rodent models as well as in human infants. However, recent evidence has demonstrated the existence of active brown adipose tissue in adult humans. These findings prompted a resurgence of research focusing on both the activation of brown adipose tissue and the “browning” of white adipose tissue, a phenomenon wherein UCP-1-mediated mitochondrial uncoupling is induced by stimuli. Multiple studies using rodent models have demonstrated that activation of brown fat or induction of browning can promote beneficial metabolic effects, and promising therapeutic targets have been identified. However, the therapeutic potential of these targets has not been confirmed due to the lack of a widely available human brown adipocyte model. Therefore, there is a pronounced need to validate existing therapeutic targets in the human system. ZenBio will address this need by providing a well characterized human brown adipocyte cell culture system to the research community and will utilize this tool to screen potential candidates for stimulation of human brown adipogenesis. The overarching goal of this project is to generate and characterize an adult human brown adipocyte cell system. Aim 1 is intended to build on our successful establishment of a human fetal brown adipocyte system in Phase 1 and use molecular and functional characterization to generate a widely available adult human brown adipocyte system. This includes establishing conditionally immortalized adult brown preadipocyte lines for use in cell-number intense research and screening. The second Aim will expand the adult system to include donors from a wide range of demographics. This Aim will also establish a database of molecular and functional characterization from this donor set that will be available to the research community. Aim 3 will establish a robust, high content/high throughput screening platform capable of multiplexing molecular and function al assays in a 384 well format. This platform will be able to screen for brown fat modulators and activators, as well as validating therapeutic targets. The goal of these three Aims is to characterize and commercialize the adult human brown adipocyte system from donors of differing BMI, age, gender and diabetic state and validate their use to identify novel targets of brown adipocyte differentiation for the treatment of obesity. These studies will result in innovative targets for human brown adipocyte activation, a crucial step for anti-obesity therapeutics.

Public Health Relevance Statement:
Project Narrative The worldwide prevalence of obesity and its related diseases is at epidemic proportions necessitating novel therapeutic approaches. The recent identification of human adult brown fat has led researchers to investigate new ways to increase this beneficial adipose tissue to deter obesity related diseases. We will generate an adult human brown adipocyte system and screening platform that can be used to discover and validate novel therapeutic modalities.

NIH Spending Category:
Biotechnology; Diabetes; Nutrition; Obesity

Project Terms:
Address; adipocyte differentiation; Adipocytes; Adipose tissue; Adrenergic Agents; Adult; Affect; Age; base; Biological; Biological Assay; Biological Markers; Biological Models; Biology; Body Weight decreased; Brown Fat; Burn injury; Cell Count; Cell Culture System; Cell Line; Cell model; Cells; commercialization; Communities; Comorbidity; Databases; demographics; Development; diabetic; Disease; drug candidate; Drug Targeting; Energy Metabolism; Epidemic; experience; fetal; Fetus; fight against; Gender; Gene Expression; Generations; glucose uptake; Goals; Heating; high throughput screening; Human; human fetus tissue; Image; immortalized cell; Incidence; Infant; innovation; lipid biosynthesis; Lipids; Measures; Mediating; Metabolic; Metabolic Diseases; Methods; Mitochondria; Modality; Modeling; Molecular; new therapeutic target; Non-Insulin-Dependent Diabetes Mellitus; novel; novel therapeutic intervention; novel therapeutics; Obesity; Obesity associated disease; obesity treatment; oxidation; Oxidative Phosphorylation; Oxygen Consumption; Patients; Performance; Phase; phase 1 study; phase 2 study; Plasma; Population; Prevalence; Procedures; Production; programs; protein expression; Protocols documentation; Provider; Quality Control; repository; Research; Research Personnel; Respiration; Rodent Model; screening; Services; Source; Stimulus; success; System; Targeted Research; Therapeutic; therapeutic target; Thermogenesis; Tissue Procurements; Tissues; tool; Translating; Triglycerides; United States; Validation; Vari