Tissu adipeux brun | EPFL Graph Search

thumb|Tissu adipeux brun chez une femme (tomographie par émission de positons.) Le tissu adipeux brun ou graisse brune est l'un des types de tissu adipeux (les autres étant le tissu adipeux blanc et la moelle hématopoïétique; et le tissu adipeux beige ou brite pour brown in white) présent chez les mammifères. Il est particulièrement abondant chez les mammifères hibernants, marins, des régions polaires et chez les nouveau-nés, mais est présent également chez l'adulte. Sa principale fonction est d'assurer, grâce à la lipolyse de ses adipocytes, la thermogenèse chez les animaux qui hibernent et les nouveau-nés qui ne sont pas encore capables de frissonner. Contrairement aux adipocytes blancs qui contiennent une gouttelette lipidique unique, les adipocytes bruns contiennent de nombreuses gouttelettes plus petites et un nombre beaucoup plus élevé de mitochondries qui contiennent du fer, donnant au tissu sa couleur brune. La graisse brune contient aussi plus de capillaires que la graisse bl

Crosstalk between Drp1 phosphorylation sites during mitochondrial dynamics and metabolic adaptation

Miriam Valera Alberni

Mitochondria are highly dynamics organelles that undergo coordinated cycles of fission and fusion, referred to as mitochondrial dynamics. Mitochondrial dynamics regulate mitochondrial bioenergetics and allow cells to adapt to changing cellular stresses and physiological challenges. The balance between different GTPase enzymes dictates the shift from interconnected tubular networks to fragmented individual units. Among them, mitochondrial fission is regulated by the mitochondrial fission orchestrator, Drp1. Drp1 function is modulated by post-translational modifications, of which the phosphorylation at two specific sites have gained most attention. Drp1 phosphorylation at the S579 site results in Drp1 recruitment to mitochondria to promote fission, whereas the research on the role of the Drp1 S600 phosphorylation have yielded contradictory results on whether it promotes fission or fusion. Importantly, the crosstalk and physiological impact of these phosphorylations is poorly understood. In this project, we focused first on elucidating the interplay between Drp1 S600 and Drp1 S579 phosphorylations. We described how Drp1 S600 phosphorylation promotes S579 phosphorylation by protecting against its dephosphorylation. The activation at both S600 and S579 sites is required to, then, promote mitochondrial fragmentation. To explore the physiological relevance of these phosphorylations, we generated a Drp1 S600A knock-in (Drp1KI) mouse model. Drp1KI mice displayed enhanced lipid oxidation rates and respiratory capacity, granting improved glucose tolerance and thermogenic capacity upon high-fat feeding. Housing mice at thermoneutrality blunted these differences, suggesting a role for the brown adipose tissue in the protection of Drp1KI mice against metabolic damage. Therefore, this work unveils for the first time the crosstalk between Drp1 phosphorylation sites and their relationship to impact on mitochondrial architecture. Moreover, we demonstrate that targeting the Drp1 S600 site can grant protection against diet-induced insulin resistance, suggesting that the modulation of these phosphorylations could be used in the treatment and prevention of metabolic diseases.

EPFL2020

Gene regulatory dynamics underlying brown fat cell differentiation

Rachana Narendra Pradhan

Adipose tissue is increasingly recognized as a dynamic, endocrine organ responsible for regulating metabolic homeostasis via the collective action of its two principal subtypes: white adipose tissue (WAT) and brown adipose tissue (BAT). Recently, the discovery of metabolically active brown fat reserves and brown in white fat (also known as "brite" or "beige" fat) in adult humans has prompted fundamental research to understand the development and function of brown adipocytes. The functional property of brown adipocytes is executed by the mitochondrial protein, Un- coupling Protein 1 (UCP1). UCP1 is responsible for uncoupling oxidative phosphorylation from ATP production thereby dissipating heat. The gene expression of Ucp1 is orchestrated by a multitude of transcriptional regulators and co-regulators that are distinct from those governing white adipocyte differentiation and function. However, in contrast to its counter- part, the white adipocyte, the gene regulatory mechanisms and transcriptional drivers of the brown adipocyte differentiation program remain elusive. Thus the focus of this thesis is to elucidate the gene regulatory network underlying brown fat cell differentiation and to decou- ple differentiation from the thermogenesis program using an integrative genomics approach. The main contributions of this work are as follows (1) construction of a comprehensive map integrating signaling, transcriptional and metabolic modules necessary for the activation of a brown adipocyte, (2) systematic, comprehensive analysis of transcriptional and chromatin state dynamics during brown fat cell differentiation leading to the identification of novel transcriptional regulators, (3) genomic characterization of the TF BCL6 during brown fat cell differentiation and (4) phenotypic characterization of a novel conditional BCL6 knockout mouse model.

EPFL2017

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