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Projekt Druckansicht

Regulation des Energiestoffwechsels durch BRITE Adipozyten

Fachliche Zuordnung Endokrinologie, Diabetologie, Metabolismus
Förderung Förderung von 2012 bis 2018
Projektkennung Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 216373792
 
Erstellungsjahr 2018

Zusammenfassung der Projektergebnisse

A tight regulation of energy homeostasis is a prerequisite for the maintenance of body weight and metabolic adaptation to changing nutritional and (patho)-physiological conditions. Given their capability to burn excess energy by uncoupling the respiratory chain from ATP synthesis, Ucp1-expressing, thermogenic brown adipose tissues may protect mammals to a certain degree from developing obesity during high caloric intake. On the other side, hyperactivity of these tissues potentially results in energy wasting and is suspected to contribute to body weight loss in cancer cachexia. Contrary to a former paradigm, substantial amounts of thermogenically active adipose tissues were recently found in discrete areas of adult humans and thus have gained attention as therapeutic targets for combating conditions of energy dysbalance. Especially, BRITE (brown-in-white) adipose tissue is of interest in this context, as its formation can be induced in energy storing white adipose depots by physiological stimuli or pharmacological compounds, and thus it might likely to be targeted by nutritional or pharmacological approaches. For exploitation of the therapeutic potential of BRITE adipose tissue, a better understanding of its differentiation and function in various settings is still urgently needed. Here, we addressed the functional role of BRITE adipose tissue in metabolic health and disease. Specifically, we have demonstrated that BRITE adipocytes improve systemic glucose utilization in an insulin-independent manner. Furthermore, we have investigated the role of specific immune cells – namely regulatory T cells and alternatively activated macrophages – in the regulation of brown fat activity. Additionally, our research contributed to the identification of a novel micro RNA that directs differentiation of human preadipocytes towards a BRITE phenotype. In-depth understanding of the molecular regulation of BRITE progenitor cells is required to exploit their therapeutic potential in the treatment of obesity and insulin resistance. Therefore we used expression profiling in a physiological model of BRITE adipocyte differentiation to identify new regulatory factors controlling the early steps of progenitor cell activation. In this way we discovered and functionally validated a signaling pathway crosstalk linking transient inflammation to the activation of BRITE progenitor cells and a transcriptional cofactor mediating sex-specific differentiation of BRITE adipocytes and insulin sensitization in the context of treatment with the antidiabetic drug rosiglitazone. In the context of the second objective we scrutinized the involvement of BRITE adipose tissue in body wasting associated to cancer cachexia. Intriguingly, in disagreement with our initial hypothesis and recent studies from labs in the US and Austria, we found no induction of Ucp1 in cachectic adipose tissue, and, more important, that Ucp1 knockout mice were not protected from cachexia. In line with this, energy expenditure in cachectic animals was not augmented, altogether supporting the hypothesis that BRITE-independent processes lead to decay of adipose tissue under these conditions. We found that under cachectic conditions, destabilization of AMPK by CIDEA interaction induces a futile cycle of lipolysis and lipogenesis in WAT. Interfering with this interaction resulted in protection from body wasting in tumor-bearing mice, thereby providing an unprecedented entry point into developing novel treatments to combat this yet incurable condition. Altogether, the Reinhart Koselleck Project reported here, yielded novel insights into the function and dysfunction of BRITE adipocytes. Our findings provide first steps in the development of innovative adipose-tissue-targeting therapies for conditions of metabolic dysbalance.

Projektbezogene Publikationen (Auswahl)

 
 

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