Biology

Dr. Devram Ghorpade
Department of Medicine, Columbia University, NY, USA

In obesity, metabolites and nutrients trigger a state of low-grade chronic inflammation termed “meta-inflammation”. Obesity associated meta-inflammation is linked to variety of comorbidities like type 2 diabetes, atherosclerosis, inflammatory bowel disease and kidney disease. Inflammatory macrophages drive meta-inflammation in distinct organs and tissues. Meta-inflammation induced pathological conditions in obesity involve an integrated cross-talk among these organs and tissues, notably, liver, adipose tissue, pancreas, brain, and skeletal muscle, via the secretion of signaling factors, or "kines". While much has been learned by studies in “kine” biology in obesity and insulin resistance, little is known about a potentially key axis, namely, how hepatokines contribute to adipose pathobiology in obesity.

We have recently discovered previously unknown hepatokine-adipose axis in obesity that affects the key endpoints of adipose inflammation and insulin resistance. As it turns out, hepatocytes secrete a soluble form of DPP4, which then interacts with its receptor (caveolin-1) on visceral adipose tissue macrophages to promote adipose inflammation and insulin resistance. Interestingly, DPP4 requires a co-factor in this process, which turns out to be factor Xa, a known macrophage inflammatory factor that acts through its receptor, PAR2. Thus, our data demonstrate that obese liver via secretory soluble DPP4 dictates adipose tissue meta-inflammation and contributes to disturbed glucose homeostasis. The identification of this pathway adds new insights into organ cross-talk that can exacerbate metabolic disarray in obesity and defines hepatic DPP4 as a potential therapeutic target for obesity-meta-inflammation induced insulin resistance.