Obesity is a major worldwide health epidemic, associated with pathological disorders such as diabetes, hypertension and atherosclerosis. By dissipating energy as heat, brown adipose tissue (BAT) plays a critical role in keeping an organism warm in response to a cold environment, and can affect adiposity by regulating key pathways in energy storage and expenditure. Accordingly, strategies designed to maintain and activate BAT, as well as promote browning of white adipose tissue (WAT), could be attractive for combating obesity. This study will investigate how the Estrogen Related Receptors (ERR?,?,?) transcriptionally modulate BAT metabolism. Extensive examination of ERR action in adipose tissue will enhance our understanding of adipose tissue biology and be important in designing novel therapeutic targets for the treatment obesity and related metabolic disorders.
Aim 1 of this proposal will assess the in vivo role of ERRs in adipose tissue by examining mice lacking ERR specifically in this tissue. It will also determine the function of lack of multiple adipose tissue, by characterizing mice lacking multiple ERRs in adipose tissue.
Aim 2 will establish gene expression signatures in ERR deficient mice by measuring transcriptional changes as well as the genomic occupancy of ERRs, by capitalizing on the availability of high context whole genome sequencing and advances in methods for chromatin immunoprecipitation.
Aim 3 will investigate an upstream signaling pathway, involving IL6-STAT3, that controls ERR? expression. Generation of novel genetic mouse models combined with next-generation sequencing and genome-wide approaches to reveal transcriptional outcomes will reveal the molecular mechanism underlying ERR action in adipose tissue and aid in design of novel therapeutic targets for obesity. The candidate's goal for the next three years is to develop an independent research program in the area of adipose biology, nuclear receptors, and metabolic physiology, and to transition into an academic faculty position. She has extensive background training in adipose tissue biology and whole-body metabolism. In the laboratory of Dr. Ronald Evans laboratory at the Salk Institute she continues to gain experience in whole- genome approaches to understand transcriptional regulation and how it controls whole body physiology. With further training in the Evans laboratory she will be able to sharpen laboratory skills such as chromatin immunoprecipitation and genome-wide analyses, methodologies that fall well into the expertise of the Evans lab. She will continue to collaborate with her co-mentor, Dr. Alan Saltiel, during this award, to acquire expertise in insulin signaling and inflammation. The candidate's long-term career goal is to become a leading independent biomedical researcher at an academic institution, investigating the molecular basis of obesity and related disorders. This award will also allow her to hone her technical skills, develop her own research niche and distinguish herself from her current mentor.

Public Health Relevance

Obesity is a major worldwide health epidemic associated with pathological disorders such as diabetes, hypertension and atherosclerosis. Understanding how brown adipose tissue (BAT) controls the activity of genes in metabolic pathways is crucial for developing treatments for these diseases. The research proposed here aims to better understand how the Estrogen Related Receptors (?,?,?) control gene expression in BAT, under different physiological and pathological conditions.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Scientist Development Award - Research & Training (K01)
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Kidney, Urologic and Hematologic Diseases D Subcommittee (DDK)
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Spain, Lisa M
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Salk Institute for Biological Studies
La Jolla
United States
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