Diet-induced obesity and insulin resistance affects the immunomodulatory function of brown adipose tissue

Rachel Nega (Düsseldorf)1, V. Flocke (Düsseldorf)2, A. Beran (Düsseldorf)1, S. Gorressen (Düsseldorf)3, U. Flögel (Düsseldorf)2, M. Grandoch (Düsseldorf)1

1Universitätsklinikum Düsseldorf Institut für Translationale Pharmakologie Düsseldorf, Deutschland; 2Universitätsklinikum Düsseldorf Institut für Molekulare Kardiologie Düsseldorf, Deutschland; 3Universitätsklinikum Düsseldorf Institut für Pharmakologie Düsseldorf, Deutschland


Brown adipose tissue (BAT), long known only for its thermogenic properties, has recently been suggested to act not only as a promising target for the treatment of obesity but also as a modulator of cardiovascular disease. Mechanistically, regulation of lipid clearance and glucose homeostasis as well as BAT`s capacity to secrete so called batokines have been discussed. However, own investigations also suggest an important role of BAT in regulating inflammatory responses.
Aim of the present study was to investigate the effects of BAT under prediabetic conditions where known alterations in BAT morphology and function occur.
Using a model of diet-induced obesity (DIO) and insulin resistance, 8-week-old male C57BL/6J mice (Janvier) were fed either a diabetogenic or control diet for 9 weeks before being subjected to cardiac ischemia/reperfusion injury (I/R). Weight gain was documented weekly and glucose tolerance tests were performed to verify the development of prediabetes. Three days prior to I/R mice underwent surgical removal of BAT or respective sham surgery. Heart function and BAT activation were measured up to three weeks post I/R by magnet resonance imaging (MRI). Scar size was determined by Gomori`s trichrome staining and circulating immune cells were analyzed by flow cytometry 3 weeks post I/R.

Compared to mice on a control diet, DIO mice showed greater weight gain and significantly reduced glucose tolerance as expected. In contrast to control diet mice, BAT activity post-I/R as determined by MRI T2 mapping was significantly impaired in DIO mice suggesting a certain loss in function of BAT during development of obesity. However, BAT ablation prior to I/R impaired cardiac function in both groups equally. Gomori staining revealed increased scar sizes and reduced mean left ventricular wall thickness in both, DIO and control diet mice.
However, circulating immune cells were still increased three weeks post-I/R in mice fed a control diet when BAT was missing while this increase was not detected in DIO mice. Specifically, neutrophils and monocytes were significantly increased in mice on a control diet compared to DIO.
Summarized, we demonstrate here that the absence of BAT significantly worsens the cardiac outcome post I/R by exaggerating the immune response. In obese mice reduced activation of BAT is observed post-I/R in this setting and also effects on the inflammatory response are blunted.
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