It’s great to have a chance to speak with Dr Nitzan Maixne and Dr Assaf Rudich. Congratulations to both of you on your new publication Role for a TNF superfamily network in human obesity.
Please give us a top-line summary of the paper which will help us better understand adipose tissue dysfunction
Adipose tissue dysfunction characterizes patients whose obesity is associated with increased risk for cardio-metabolic morbidity, and therefore defines a high health-risk obesity phenotype. The new paper reports, using strictly human tissues and experimental model systems, a newly-identified mechanism that contributes to adipose tissue dysfunction in obesity. In essence, it describes a paracrine (cell-to-neighbouring cell) communication network between different cell-types comprising adipose tissue, which interact via cytokines that belong to the TNF-superfamily of inflammatory cytokines.
While TNF has been the first cytokine implicated in linking adipose tissue inflammation and insulin resistance, additional family members of this cytokine are increasingly being implicated in mediating adipose tissue dysfunction. In our study, we discovered in an unbiased manner the contribution of TNF-superfamily member 10, or TRAIL, which has been already implicated in adipose tissue biology and dysfunction, and TNF-superfamily member 15, or TL1A, which has only recently been introduced as a player in adipose tissue in obesity. The two factors and their receptors mediate an intricate, dysfunctional communication, between adipocytes, adipose tissue T-lymphocytes, and macrophages.
Can you describe your novel contribution here?
The novelty of this study stems from the prior recognition of the role of E2F1 in adipose tissue biology. E2F1 is a well-known cell-cycle regulator implicated in cancer, which we have previously established as a mediator of adipose tissue dysfunction in obesity. It activates, acting as a transcription factor in the non-proliferating adipocytes, two pathogenic pathways in adipose tissue – the ASK1 MAP kinase pathway, and autophagy. However, these two pathways do not mediate E2F1’s full role in adipose tissue dysfunction. To discover additional pathways, we conducted RNA-sequencing study of visceral adipose tissue from pairs of people with obesity matched for age, sex and BMI (all above 30 kg/m2), but who were disparate in the expression level of E2F1. This analysis had lead to the discovery of TRAIL and TL1A as putative mediators. We could then propose, using human cells and tissues, the following: Increased E2F1 in adipocytes up-regulates TRAIL. TRAIL secreted from adipocytes induces enhanced expression and secretion of TL1A, specifically from adipose tissue T-lymphocytes. TL1A, in turn, induces adipocyte dysfunction (impairs insulin sensitivity, lipolysis, and adipokine production), and in adipose tissue macrophages induces inflammatory polarization and foam cell biogenesis. Jointly, we propose an E2F1-associated, TNF-superfamily-mediated paracrine network as a novel mechanism for adipose tissue dysfunction in obesity.
What will be the significance of understanding molecular signatures of obesity subtypes in clinical management?
As the obesity pandemic spreads, it becomes clearer that the heterogeneity of this disease no longer enables us to clinically relate to obesity merely by BMI criteria (the single parameter by which obesity is currently defined). Obesity is unlikely a single entity- not in the degree of health risks it imposes, nor in the likelihood for remission and response to various interventions. However, efficient tools for the identification of distinct obesity subtypes are yet to be established, laying the basis for the motivation to uncover molecular signatures for obesity “sub-types”. Such signatures will hopefully assist in closing the gap between obesity medicine and modern oncology, and enable using molecular signatures to deliver more precision/personalized care.