Project 03

Regulation of adipogenesis and adipocyte fate by inflammatory signalling

• Principial Investigators:
  • TUD: Peter Mirtschink & Triantafyllos Chavakis
  • ETH: Christian Wolfrum & Carla Horvath
• Students:
  • TUD: Rajeshwari Choudhury Nath (1st year-PhD student), Rona Berit Geissler (Dr. med. student)

  • ETH: Clarisse Engl (2nd year-PhD student)

Background: Obesity is accompanied by altered function of precursor populations in the white and brown adipose tissue (WAT and BAT respectively) that may lead to adipose tissue changes, such as hyperplasia (increase in cell number) and/or hypertrophy (increase in cell size), fibrosis and reduced beige and brown thermogenic adipogenesis. These alterations in adipocyte precursor function hence underlie obesity-related metabolic dysregulation of the adipose tissue promoting obesity-associated metabolic disease. Evidence from epidemiologic studies suggests that preceding inflammatory events, such as earlier infection and/or antibiotic exposure increases the 
risk of obesity in childhood and in adult life. While this has been partially attributed to 
altered microbiome, the exact mechanisms remain unclear. Specifically, it is less well understood how inflammatory signalling, triggered e.g. by a preceding infection or inflammation may affect adipocyte precursor fate and their subsequent reactions to an obesogenic high-caloric diet. We (Chavakis and Mirtschink group) are interested in how inflammation in the adipose tissue may affect the development of metabolic dysregulation. In addition, we have substantially contributed to the understanding of the new immunological principle of trained immunity, which defines a form of inflammatory memory. Specific inflammatory triggers may induce, via epigenetic rewiring, a higher preparedness of innate immune cells, which then show stronger responses upon 
a future secondary challenge. Interestingly, inflammatory memory has been described in 
parenchymal cells as well. The Wolfrum group aims to identify adipocyte precursor populations for both WAT and BAT in vivo and furthermore, to elucidate molecular mechanisms driving preadipocytes proliferation, commitment and differentiation as well as activity of mature white and brown adipocytes. In this context, we have recently identified a rare subpopulation of adipocytes that increases in abundance at higher temperatures and regulates the activity of neighbouring adipocytes through modulation of their thermogenic capacity. Additionally, we have shown that seasonal or experimental cold exposure induces epigenetic reprogramming of the sperm resulting in hyperactive BAT in the offspring and in improved adaptation to over-nutrition andhypothermia.

Aims: In this project, we hypothesize that inflammatory memory of adipocyte precursors may affect the later development of pathologic obesity. We will assess if a preceding inflammatory event may epigenetically modify adipocyte precursors, which then react in a different fashion to a future obesogenic high-caloric diet. Using mouse models of acute and chronic inflammation or acute infection we aim to study whether (1) an earlier inflammatory trigger, e.g. LPS (Chavakis, Mirtschink) or (2) an earlier infection (Wolfrum) affects white and brown adipocyte precursors with regards to their functions, such as proliferation and differentiation, thereby contributing to obesity and metabolic dysfunction at later time points. To this end, we will thoroughly assess the temporal 
dynamics of adipose tissue composition and function.

Added value through the collaboration between Dresden & Zurich: The Chavakis and 
Mirtschink group are closely collaborating in multiple projects. The Chavakis group has unique expertise in innate immunity and animal models of inflammation and metabolic 
diseases. The Mirtschink group has expertise in cellular stress and metabolic alterations under inflammatory stimuli and the use of integrated – omics for deciphering the respective mechanisms. The Wolfrum group has unique expertise in the molecular mechanisms and cellular heterogeneity of adipose tissue. Combining these complementary areas  will provide knowledge on the possible involvement of inflammatory memory on adipose tissue composition and function, as possible contributors to metabolic dysregulation.

Synergies: We will collaborate with project 1 to assess the cross-talk between the adrenal gland and adipose tissue (AT) maturation and dysfunction. We will interact with project 2 to study LPS-or infection-induced necroptosis in AT, as a highly inflammatory form of cell death. Furthermore, we will consider in collaboration with projects 5, 7 the role of gut microbiota and with project 8 the role of dietary interventions in the regulation of systemic and AT inflammation in relation to infection and metabolic state.