Project Details
Projekt
A novel regulator of metabolic disease
Subject Area
Immunology
Endocrinology, Diabetology, Metabolism
Endocrinology, Diabetology, Metabolism
Term
since 2023
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 503693942
Type 2 immunity modulates obesity-related metabolic disease, however the implicated mechanisms remain elusive. We found that IL-4 targets adipocyte progenitors (AP) and inhibits their differentiation, thereby protecting mice against diet-induced obesity. Moreover, IL-4 promotes polyamine metabolism by increasing the expression of Arginase 1 (Arg1) and Antizyme inhibitor 2 (Azin2) in AP. In accordance, arginine metabolism is downregulated in the obese compared to the lean adipose tissue (AT). Strikingly, Azin2 deficient mice display aggravated obesity, reduced energy expenditure, liver steatosis, as well as increased oxidative stress and cellular senescence in the AT. Mechanistically, polyamine metabolism is mediated by ARG1, ornithine decarboxylase 1 (ODC1) and spermidine/spermine-N1-acetyltransferase (SSAT), promoted by AZIN2 and upregulated by IL-4, leading to polyamine acetylation and consumption of acetyl-coenzyme A (acetyl-CoA). Silencing of Arg1, Odc1 or Ssat or Azin2 knockout increase adipogenic hallmarks, while Azin2 deficiency results in enhanced senescence in AP. Hence, our findings underscore an important role of polyamine metabolism in AT homeostasis. In the here presented research programme we will validate the significance of polyamine metabolism in obesity-related metabolic disease and reveal its role as a mediator of the effects of type 2 immunity in the AT through a multi-angle approach using different in vivo and in vitro models, genetically engineered mice and human data. These approaches will include 1) engagement of mice with AP- or adipocyte-specific Arg1 or Azin2 deficiency 2) in vivo treatments with (acetylated) polyamines 3) different models of activation of type 2 immunity (IL-4 treatment, parasite infections, hair follicle morphogenesis) 4) use of mice with AP-specific Il-4ra deficiency 5) study of different AT depots (inguinal subcutaneous, gonadal, mesenteric and dermal) 6) analysis of human biopsies and data and correlation with metabolic disease 7) obesity- and aging-induced AT dysfunction and 8) in vitro approaches using primary AP from Arg1- or Azin2-deficient mice or silenced via siRNA for different polyamine metabolism genes. Epigenetic (histone acetylation) and posttranslational (non-histone protein acetylation) mechanisms underlying the effects of IL-4 and polyamine metabolism in the AT will be dissected on the basis of our findings showing that polyamine metabolism is a critical regulator of acetyl-CoA. In conclusion, our work will highlight polyamine metabolism as a novel regulator of obesity-related metabolic disease and potentially pave the way for new approaches in its prevention.
DFG Programme
Research Grants
