#1 GPS2 Deficiency Triggers Maladaptive White Adipose Tissue Expansion in Obesity via HIF1A Activation
Hypertrophic white adipose tissue (WAT) represents a maladaptive mechanism linked to the risk for developing type 2 diabetes in humans. However, the molecular events that predispose WAT to hypertrophy are poorly defined. Here, we demonstrate that adipocyte hypertrophy is triggered by loss of the corepressor GPS2 during obesity. Adipocyte-specific GPS2 deficiency in mice (GPS2 AKO) causes adipocyte hypertrophy, inflammation, and mitochondrial dysfunction during surplus energy. Increased mitochondrial activity and biogenesis is an essential biological processinvolved in WAT remodeling and browning following cold exposure and β-adrenergic receptor stimulation. To visualize the faults in mitochondrial activity and adaptation in vivo, WT and GPS2 AKO mice were subjected either to treatment with an agonist of β3 adrenergic receptor or cold exposure for 5 days. Cold exposure or β3-adrenergic stimulation provoked, in WT mice, increased mitochondrial biogenesis and adipose tissue beiging characterized by increasing MTCO2 and UCP-1 staining, respectively. In contrast, GPS2 AKO mice upon those conditions did not respond as WT control mice. Adipose tissue maladaptation to cold exposure of GPS2 AKO mice was characterized at the whole-body level by a significant decrease in body temperature and alteration of O2 consumption. Collectively, these data suggest that the dysfunctional adipose tissue observed in GPS2 AKO mice could be in part driven by disrupted mitochondrial activity .We propose therefore that the obesity-associated loss of GPS2 in adipocytes predisposes for a maladaptive WAT expansion and a pro-diabetic status.
#2 GPS2 Deficiency in Adipocytes Potentiates HIF1A-Dependent Pathways
RNA sequencing from isolated adipocytes of eWAT from WT control and GPS2 AKO mice fed an HFD for 12 weeks revealed that 2,239 transcripts were induced in isolated adipocytes of eWAT from GPS2 AKO mice relative to WT mice. Among these upregulated transcripts were genes involved in inflammation, as expected, but also genes likely involved in adipose tissue expansion,suggesting a crucial function of GPS2 in adipocyte remodeling. Network analysis of genes significantly increased in eWAT adipocytes of GPS2 AKO mice indicated that HIF1A-dependent pathways could play a central role in the disrupted adipocyte adaptation in GPS2 AKO mice.
#3 Early macrophage response to obesity encompasses Interferon Regulatory Factor 5 regulated mitochondrial architecture remodelling
We demonstrate that Interferon Regulatory Factor 5 (IRF5) is a key regulator of macrophage oxidative capacity in response to caloric excess. ATMs from mice with genetic-deficiency of Irf5 are characterised by increased oxidative respiration and mitochondrial membrane potential. We find that the highly oxidative nature of Irf5-deficient macrophages results from transcriptional de-repression of the mitochondrial matrix component Growth Hormone Inducible Transmembrane Protein (GHITM) gene. The Irf5-deficiency-associated high oxygen consumption could be alleviated by experimental suppression of Ghitm expression. ATMs and monocytes from patients with obesity or with type-2 diabetes retain the reciprocal regulatory relationship between Irf5 and Ghitm. Thus, our study provides insights into the mechanism of how the inflammatory transcription factor IRF5 controls physiological adaptation to diet-induced obesity via regulating mitochondrial architecture in macrophages.
