GRK2 levels in myeloid cells modulate adipose-liver crosstalk in high fat diet-induced obesity

Myeloid GRK2 Regulates Obesity-Induced Endothelial Dysfunction by Modulating Inflammatory Responses in Perivascular Adipose Tissue

“…To directly address whether GRK2 dosage in myeloid cells might have a role in vascular functionality and damage, we used a HFD-induced obesity model comparing control animals with those with a selective downregulation of GRK2 in this cell lineage (LysM-GRK2 +/− ). We have recently shown that a 12 week-long HFD feeding induced obesity in both control and LysM-GRK2 +/- animals to the same extent but only deteriorated glucose tolerance, caused hyperglycemia, and provoked insulin resistance and inflammation in liver and adipose tissue in control mice, while LysM-GRK2 +/− animals maintained smaller adipocytes [ 23 ]. Regarding vascular function, we show here that, in aortic rings devoid of PVAT, endothelium-dependent relaxation to acetylcholine was similar in control and LysM-GRK2 +/− mice, both in animals fed a normal diet (ND) ( Figure 2 A) and in animals fed a HFD ( Figure 2 B).…”

“…Experiments were performed on 5-month-old male control mice and mice with a reduction of around 50% in GRK2 levels in myeloid cells ( LysM-GRK2 +/ − ) [ 23 ]. In particular, transgenic male mice overexpressing a nuclear-localized Cre recombinase inserted into the first coding ATG of the lysozyme 2 gene (Lyz2) (B6.129P2-Lyz2tm1(cre)Ifo/J), obtained from Jackson Laboratories (Bar Harbor, ME, USA), were mated to floxed homozygous GRK2 (GRK2 f/f ) female mice.…”

“…In particular, transgenic male mice overexpressing a nuclear-localized Cre recombinase inserted into the first coding ATG of the lysozyme 2 gene (Lyz2) (B6.129P2-Lyz2tm1(cre)Ifo/J), obtained from Jackson Laboratories (Bar Harbor, ME, USA), were mated to floxed homozygous GRK2 (GRK2 f/f ) female mice. GRK2 f/Δ LysM-Cre −/− controls (referred to as control mice) and GRK2 f/Δ LysM-Cre +/− (referred to as LysM-GRK2 +/− ) offsprings were used and genotyped as described [ 23 ]. Animals were bred under controlled conditions at 22 ± 2 °C, with a relative humidity of 50 ± 10% in a 12h light/dark cycle with free access to food and water in the animal facility of the Centro de Biología Molecular Severo Ochoa (Madrid, Spain).…”

“…Moreover, it has been suggested that GRK2 may have a potential role in the onset or development of inflammatory disorders or in human pathologies with an inflammatory basis [ 16 ]. In this context, we recently reported that a reduction of GRK2 levels in myeloid cells prevents the development of glucose intolerance and hyperglycemia after a high fat diet (HFD) by downregulating a pro-inflammatory macrophage profile [ 23 ]. Moreover, conditioned media of macrophages that are hemizygous for GRK2 and treated with lipopolysaccharide (LPS) has a reduced pro-inflammatory effect on naïve macrophages.…”

“…Moreover, conditioned media of macrophages that are hemizygous for GRK2 and treated with lipopolysaccharide (LPS) has a reduced pro-inflammatory effect on naïve macrophages. So, reducing GRK2 levels in myeloid cells is, per se, able to attenuate pro-inflammatory activation of macrophages and preserve physiological features of adipose and hepatic tissues in the face of a HFD [ 23 ].…”