Human obesity represents a serious world-wide health problem. One consequence of obesity is the development of metabolic syndrome, characterized by insulin resistance and hyperglycemia, that can lead to ? cell dysfunction and type 2 diabetes. It is therefore important that we gain an understanding of the physiology and pathophysiology of the development of obesity because this knowledge represents a basis for the design of potential therapeutic interventions. Recent studies have identified increased energy expenditure caused by adipose tissue thermogenesis as an important contributing factor that can limit obesity development. The sympathetic nervous system promotes adipose tissue thermogenesis by activating brown adipose tissue. The magnitude of this response can be increased by the presence of brown-like adipocytes in white adipose tissue depots. These brite/beige adipocytes are more common in sub-cutaneous adipose tissue compared with visceral adipose tissue, and their presence is strongly induced by exposure to cold. Control of beige/brite adipocytes ? for example, using pharmacological tools ? represents a potential therapeutic option for the treatment of obesity. Consequently, it is important that we gain an understanding of molecular mechanisms that contribute to adipose tissue thermogenesis. This knowledge is critical for identifying possible molecular targets that could be employed for therapeutic intervention. Significant progress has been achieved towards defining beige/brite cell development and function, including the role of signaling pathways and transcription factors. However, there are significant gaps in our knowledge. Recent studies in my laboratory have uncovered a role for alternative pre-mRNA splicing in the regulation of adipose tissue thermogenesis. We have identified widespread changes in alternative pre-mRNA splicing in white adipocytes following consumption of a high fat diet. Bioinformatic analysis identified NOVA binding sites in a large fraction of regulated adipocyte pre-mRNA splicing events. Indeed, we found that NOVA expression is regulated by diet-induced obesity in both rodents and humans. To test the role of NOVA proteins, we established Nova1LoxP/LoxP and Nova2LoxP/LoxP mice and studied the effect of NOVA-deficiency in adipocytes. We found that NOVA-deficiency caused ?browning? of white adipose depots, increased adipose tissue thermogenesis, and protection against diet-induced obesity and metabolic syndrome. These studies identify pre-mRNA splicing as a potential target for therapeutic intervention in obesity-induced metabolic syndrome. Importantly, previous studies have established pre-mRNA splicing as a pharmacologically tractable target for therapeutic intervention in diseases. The overall goal of this research program is to identify molecular mechanisms that account for the function of NOVA pre-mRNA splicing factors in adipocytes. Achievement of this goal will increase understanding of the molecular response to obesity. We anticipate that the successful completion of this research program will lead to the identification of new mechanisms that contribute to the obesity response. This knowledge may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type 2 diabetes.

Public Health Relevance

The goal of this research program is to understand metabolic stress responses of adipose tissue. We propose to combine physiological analysis together with quantitative analysis of pre-mRNA splicing to define novel molecular mechanisms that mediate adipose tissue stress responses. The knowledge obtained may represent a basis for the design of novel therapeutic strategies for the treatment of metabolic syndrome and type 2 diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK112698-01A1
Application #
9401372
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Haft, Carol R
Project Start
2017-07-17
Project End
2021-06-30
Budget Start
2017-07-17
Budget End
2018-06-30
Support Year
1
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Barutcu, Seda Avcioglu; Girnius, Nomeda; Vernia, Santiago et al. (2018) Role of the MAPK/cJun NH2-terminal kinase signaling pathway in starvation-induced autophagy. Autophagy 14:1586-1595
Lessard, Sarah J; MacDonald, Tara L; Pathak, Prerana et al. (2018) JNK regulates muscle remodeling via myostatin/SMAD inhibition. Nat Commun 9:3030
Girnius, Nomeda; Edwards, Yvonne J K; Davis, Roger J (2018) The cJUN NH2-terminal kinase (JNK) pathway contributes to mouse mammary gland remodeling during involution. Cell Death Differ 25:1702-1715
Girnius, Nomeda; Edwards, Yvonne Jk; Garlick, David S et al. (2018) The cJUN NH2-terminal kinase (JNK) signaling pathway promotes genome stability and prevents tumor initiation. Elife 7:
Kant, Shashi; Standen, Claire L; Morel, Caroline et al. (2017) A Protein Scaffold Coordinates SRC-Mediated JNK Activation in Response to Metabolic Stress. Cell Rep 20:2775-2783
Martínez-Sánchez, Noelia; Seoane-Collazo, Patricia; Contreras, Cristina et al. (2017) Hypothalamic AMPK-ER Stress-JNK1 Axis Mediates the Central Actions of Thyroid Hormones on Energy Balance. Cell Metab 26:212-229.e12
Girnius, Nomeda; Davis, Roger J (2017) JNK Promotes Epithelial Cell Anoikis by Transcriptional and Post-translational Regulation of BH3-Only Proteins. Cell Rep 21:1910-1921