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The role of the transcriptional regulator BCL6 in adipose tissue development and remodeling

Teresa Didonna

The adipose tissue is increasingly recognized for the important role it plays in various diseases and pathological conditions, such as obesity, diabetes, cardiovascular diseases, osteoporosis, cancer, and aging. Despite its long-held reputation for being a simple fat storage tissue, we now know the adipose tissue is a singular organ playing a crucial role in whole-body metabolism and energy homeostasis. Understanding the development and functioning of adipose tissue and, in particular, of its structural and functional fat depots, is crucial to understanding human health and disease, and can pave the way for personalized therapeutic and preventive approaches. Transcription factors are key regulators of adipose tissue biogenesis, development, and responses to changes in environmental stimuli such as feeding, fasting, and exercise. The transcription repressor BCL6 - well known in immunology and cancer - has been recently linked to adipogenesis and metabolism. In the context of this thesis, in order to better understand the role of BCL6 in adipose tissue development and remodeling, we sought to further investigate the physiological function of BCL6 in white and brown adipose tissue. We developed and characterized a fat-specific conditional knockout mouse model for Bcl6 (Bcl6 FKO), and a Pdgfra-Cre driver was used to obtain in vivo ablation of Bcl6 in adipogenic precursors and stem cells (ASPCs). We discovered that ablation of Bcl6 in adipocyte precursors has a major impact on white fat mass and its distribution in the bodies of mice. Moreover, being fed a standard and a high-fat diet has a prominent effect on visceral adipose tissue, the mass of which was significantly reduced compared to that of control mice. Additionally, Bcl6 FKO mice did not demonstrate sensitivity to high-fat diet-induced mass gain and related comorbidities, such as hepatic steatosis and glucose-homeostasis alterations. The increased number of adipocytes observed in the gonadal adipose tissue occurred without increasing overall adiposity and body weight compared to control mice under a high-caloric diet regime. In conclusion, Bcl6 FKO mice represent a lean mouse model with a healthy balance between subcutaneous and visceral white adipose tissue depots. BCL6 could be an interesting adipose-specific target for therapeutic interventions in the context of obesity and related metabolic dysfunctions.

EPFL2019