The role of hyaluron in beige adipogenesis

PROJECT SUMMARY/ABSTRACT Enhancing adipose tissue thermogenesis to tilt energy balance toward net expenditure has great potential to promote weight loss and treat metabolic milieus in humans. Cold exposure and β3-adrenergic receptor (AR) agonist treatment are commonly used to increase adipose tissue thermogenesis and beiging in mice. However, cold exposure-induced adipose tissue beiging predominantly recruits new beige adipocytes, while β3-AR agonists primarily promote white adipocytes to convert to beige adipocytes. Given a species difference between mice and humans in adipocyte β3-AR expression, β3-AR agonists that had remarkable efficacy in mice in promoting lipolysis and enhancing energy expenditure failed to translate into persistent weight loss and improved metabolic function in humans. So, novel approaches to promote the recruiting of new thermogenic beige adipocytes in humans are particularly interesting for developing new drugs to enhance adipose tissue thermogenesis. Our preliminary data suggest hyaluronan (HA), a polysaccharide secreted by cells, may play a crucial role in cold-induced de novo beige adipogenesis. Using several new mouse models we have generated, we showed that HA secreted within the subcutaneous white adipose tissue enhanced cold-induced adipose tissue beiging, and digestion of HA significantly reduced this process. In vitro experiments suggest HA plays a vital role in adipose progenitor cell (APC) proliferation and differentiation into beige adipocytes. Importantly, we found that aged mice had much lower HA levels in the subcutaneous white adipose tissue, which may highly correlate with the age-related decrease of white adipose tissue beiging and thermogenesis. Several critical links are still missing: A. How does cold stimulate APC to produce HA? B. Does HA directly enhance de novo beige adipogenesis in mice? C. Can we target HA to enhance thermogenesis and improve metabolic health in aged individuals? To answer these questions, we propose to determine whether cold exposure promotes APC HA production through an Adrb1-Has1 axis (Aim 1) and whether APC HA production promotes de novo beige adipogenesis and adipose tissue beiging (Aim 2). We will also determine the metabolic effects of HA-mediated APC proliferation and adipose tissue beiging in diet-induced obese and aged mice (Aim 3). Altogether, the proposed study will provide novel insights into how APC HA production mediates de novo beige adipogenesis and how it could be targeted to treat metabolic diseases.