The rates of obesity, which is defined as an excessive increase in white adipose tissue (WAT) mass, has increased rapidly over the last several decades and today 65% of the adult population in the U.S. is overweight with more than 30% of the population meeting the criteria for obesity. As the weight of the nation has increased, so have the incidences of many obesity-linked disorders, such as diabetes, cardiovascular disease and certain types of cancer. Despite the importance of WAT in normal physiology and disease, we understand little of the cellular and molecular mechanisms that regulate WAT mass in vivo. WAT is composed of several subcutaneous and visceral depots that are pertinent to the study of obesity. The differential accumulation of excessive WAT in specific depots is associated with differential risks of developing diabetes and other obesity-associated pathologies. However, the mechanisms that control WAT mass in distinct depots is not well understood. Therefore, establishing the differences in cellular and molecular events that regulate WAT mass in separate WAT depots will lead to a better understanding of obesity and how excessive WAT leads to the development of secondary pathologies. Adipocyte number increases in obesity, but this increased adipocyte number is maintained even after extreme weight loss. We have recently determined there is an obesity-specific mechanism of adipogenesis. The objective of this proposal is to determine the mechanisms that govern adipocyte formation in different physiologically relevant contexts. We hypothesize that distinct regulatory mechanisms control depot-specific adipogenesis in development and obesity. There are numerous conditions that are known to affect WAT mass and function, such as sex and anatomic location. The specific mechanisms that drive adipocyte formation in these different contexts likely influence the function of the resulting adipocytes, impacting their contribution to normal physiology and disease. Here we will define the mechanisms that drive adipocyte hyperplasia in both males and females, building a base of knowledge for future studies of the physiologic impact of these aberrant forms of adipogenesis. These studies may lead to the development of novel, sex-specific strategies for prevention and treatment of obesity and obesity-associated diseases.

Public Health Relevance

The obesity epidemic is one of the leading public health challenges as several diseases are associated with obesity, including diabetes, cardiovascular disease and cancer. The goal of this proposal is to identify processes within fat that regulate fat mass, and to determine how these processes are perturbed on obesity. These studies will result in a better understanding of how increased fat mass impacts obesity-associated diseases and lead to the development of novel sex-specific therapies for the treatment and prevention of obesity and obesity-related disease in men and women.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Yale University
Veterinary Sciences
Schools of Medicine
New Haven
United States
Zip Code
Sebo, Zachary L; Jeffery, Elise; Holtrup, Brandon et al. (2018) A mesodermal fate map for adipose tissue. Development 145:
Zwick, Rachel K; Rudolph, Michael C; Shook, Brett A et al. (2018) Adipocyte hypertrophy and lipid dynamics underlie mammary gland remodeling after lactation. Nat Commun 9:3592
Price, Nathan L; Singh, Abhishek K; Rotllan, Noemi et al. (2018) Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance. Cell Rep 22:2133-2145
Rivera-Gonzalez, Guillermo C; Shook, Brett A; Andrae, Johanna et al. (2016) Skin Adipocyte Stem Cell Self-Renewal Is Regulated by a PDGFA/AKT-Signaling Axis. Cell Stem Cell 19:738-751
Jeffery, Elise; Wing, Allison; Holtrup, Brandon et al. (2016) The Adipose Tissue Microenvironment Regulates Depot-Specific Adipogenesis in Obesity. Cell Metab 24:142-50
Price, Nathan L; Holtrup, Brandon; Kwei, Stephanie L et al. (2016) SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation. Mol Cell Biol 36:1180-93
Jeffery, Elise; Church, Christopher D; Holtrup, Brandon et al. (2015) Rapid depot-specific activation of adipocyte precursor cells at the onset of obesity. Nat Cell Biol 17:376-85
Berry, Ryan; Jeffery, Elise; Rodeheffer, Matthew S (2014) Weighing in on adipocyte precursors. Cell Metab 19:8-20
Berry, Ryan; Church, Christopher D; Gericke, Martin T et al. (2014) Imaging of adipose tissue. Methods Enzymol 537:47-73
Jeffery, Elise; Berry, Ryan; Church, Christopher D et al. (2014) Characterization of Cre recombinase models for the study of adipose tissue. Adipocyte 3:206-11

Showing the most recent 10 out of 16 publications