?Obesity has reached epidemic proportions in the U.S. and plays a major role in the development of type 2 diabetes, dyslipidemia, and cardiovascular disease. There remains a very significant need for better non- surgical treatments. While most weight loss agents rely on suppressing appetite to reduce caloric intake, strategies that can safely enhance energy expenditure have the potential to effectively treat obesity. Brown adipose tissue (BAT) is a thermogenic tissue that uniquely expresses mitochondrial UnCoupling Protein-1 (UCP1). This protein dissipates the electrochemical gradient in the mitochondria of brown adipocytes as heat. It is increased upon exposure to low temperatures, and plays an important role in the maintenance of body temperature and energy balance in rodents. BAT is also a flexible tissue that normally enlarges or atrophies over time depending on environmental temperature. In many different rodent models, enhancement of BAT mass has convincingly been shown to lead to weight loss and diabetes resistance. While BAT was until recently thought to be effectively nonexistent in adult humans, data obtained in the past several years with PET imaging show that adults in fact have significant BAT, and that this tissue is functional. Other data demonstrate that the amount of active BAT in individuals is strongly correlated with leanness and that the genetic locus most tightly linked with general obesity causes defective recruitment of new brown adipocytes. Until recently no brown adipocyte stem cell had been identified. We discovered a population of human skeletal muscle-resident brown adipocyte progenitors that under appropriate conditions become fully functional brown adipocytes. Following differentiation these cells have high levels of UCP1 and a very high metabolic rate. Using the progenitors we developed an assay for identifying compounds that recruit new, mature brown adipocytes. We then used this to screen a collection of approved drugs and found several that potently recruit brown adipocytes. These hits were validated with dose response testing. In the proposed work, we aim to further characterize these compounds for potential use as anti-obesity therapeutics. We will evaluate their suitability for development first in vitro, followed by studies in a highly predictive animal model of obesity and insulin resistance. If this work is successful, we plan to rapidly advance into a proof of concept clinical study with a potential brown fat recruiting product candidate for the treatment of obesity and diabetes.
Public Health Relevance Statement: Public Health Relevance: Obesity has reached epidemic proportions in the U.S. and globally. While most weight loss agents rely on suppressing appetite to reduce caloric intake, increasing energy expenditure is another approach to weight control. Brown adipose tissue (BAT) is a recruitable, thermogenic tissue with the capacity to utilize large amounts of fat and glucose, and which is present in reduced amounts in obese patients. We discovered a human progenitor/stem cell for BAT and have used this as a tool to discover approved drugs with the ability to increase the formation of human brown adipocytes. Here we propose to further evaluate these compounds in vitro, and subsequently in vivo, to attempt to identify the compound combinations that most effectively recruit brown adipocytes in a highly predictive animal model of obesity and insulin resistance. In doing so we anticipate that this work could identify a potential product candidate that can be rapidly and relatively inexpensively advanced into a proof of concept clinical study, with the aim of increasing brown fat and treating obesity i patients.
Project Terms: Acute; Adipocytes; Adipose tissue; Adult; Agonist; Animal Model; Animals; Area; Atrophic; Back; base; Biological Assay; Body Temperature; Body Weight; Body Weight decreased; Brown Fat; Cardiovascular Diseases; Cell Differentiation process; Cells; Clinical Research; cold temperature; Collection; Data; Desire for food; Development; Diabetes Mellitus; Diet; Dose; Drug Combinations; Dyslipidemias; energy balance; Energy Intake; Energy Metabolism; Epidemic; Exposure to; Fatty acid glycerol esters; flexibility; Genetic; Glucose; glucose metabolism; Glucose tolerance test; Goals; Gold; Harvest; Heating; Housing; Human; human data; human subject; In Vitro; in vitro testing; in vivo; Individual; Insulin; Insulin Resistance; Intention; Lead; Libraries; Life; Link; lipid biosynthesis; Maintenance; Masks; metabolic rate; Mitochondria; mitochondrial uncoupling protein; Monitor; mouse model; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; obesity treatment; Operative Surgical Procedures; patient population; Patients; Pharmaceutical Preparations; Phase; Play; Population; Positron-Emission Tomography; PPAR gamma; Prediabetes syndrome; progenitor; Proteins; public health relevance; Records; Recruitment Activity; reduced food intake; Resistance; response; Rodent; Rodent Model; Role; rosiglitazone; Safety; Science; screening; Secondary to; Serum; Skeletal Muscle; Specificity; Stem cells; success; System; Temperature; Testing; Therapeutic; Thermogenesis; Thinness; Time; Tissues; tool; uncoupling protein 1; Weight; Weight maintenance regimen; Weight-Loss Drugs; Work
