Hyaluronan mediates cold-induced adipose tissue beiging

Adipose tissue beiging refers to a process through which beige adipocytes emerge in classical white adipose tissue depots. Beige adipocytes dissipate chemical energy and secrete adipokines like classical brown adipocytes to improve systemic metabolism, which offers benefits for people with obesity and metabolic diseases. Cold exposure and β3-adrenergic receptor (AR) agonist treatment are two commonly used stimuli for increasing beige adipocytes in mice, but their underlying biological processes are different. Transcriptional analysis of inguinal white adipose tissue (iWAT) has revealed that changes in extracellular matrix (ECM) pathway genes are specific to cold exposure. Hyaluronic acid (HA), a non-sulfated linear polysaccharide produced by nearly all cells, is one of the most common components of ECM. We found that cold exposure significantly increases iWAT HA levels while β3-AR agonist CL316,243 fails to do so. Increasing HA level in iWAT by Has2 overexpression significantly increases cold-induced adipose tissue beiging; in contrast, decreasing HA by Spam1 overexpression, which encodes a hyaluronidase that digests HA, significantly decreases cold-induced iWAT beiging. All of these data implicate a role of HA in promoting adipose tissue beiging that is unique to cold exposure. Given the failure of β3-AR agonists in clinical trials for obesity and metabolic diseases, increasing HA could serve as a new approach to recruiting more beige adipocytes to combat metabolic diseases. To understand how HA may mediate cold-induced adipose tissue beiging, we performed RNA-sequence analysis on iWAT harvested from Apn-Has2 (overexpressed Has2 in adipose tissue) or Apn-PH20 (overexpressed Spam1 in adipose tissue) compared to their respective littermate Apn-rtTA controls. Transgene expressions were induced by supplementing 200 mg/kg doxycycline in the chow diet for five days for all mice, which resulted in no divergence of body weight or other metabolic phenotypes, allowing us to understand the primary effect of changes in HA levels on gene expression.