Possible Involvement of Adipose Tissue in Older and Obese Diabetic Patients with Coronavirus SARS-CoV-2 Infection (COVID-19) via GRP78 (BIP/HSPA5): Significance of Hyperinsulinemia Management in COVID-19

Shin, Jihoon; Toyoda, Shinichiro; Nishitani, Shigeki; Fukuhara, Atsunori; Kita, Shunbun; Otsuki, Michio; Shimomura, Iichiro

Aging, obesity and diabetes are major risk factors for the severe progression and outcome of SARS-CoV-2 infection (COVID-19), but the underlying mechanism is not yet fully understood. In this study, we found that the SARS-CoV-2 spike protein physically interacts with cell surface GRP78, which promotes the binding to and accumulation in ACE2-expressing cells. GRP78 was highly expressed in adipose tissue and increased in older and obese diabetic human and mouse subjects. The overexpression of GRP78 was attributed to hyperinsulinemia in adipocytes, which was in part mediated by the stress-responsive transcription factor XBP-1s. Management of hyperinsulinemia by pharmacological approaches, including metformin, SGLT2 inhibitor or ß3-adrenergic receptor agonist, decreased GRP78 gene expression in adipose tissue. Environmental interventions, including exercise, calorie restriction, fasting or cold exposure, reduced the gene expression of GRP78 in adipose tissue. This study provides scientific evidence for the role of GRP78 as a binding partner of the SARS-CoV-2 spike protein and ACE2, which might be related to the severe progression and outcome of COVID-19 in older and obese diabetic patients. The management of hyperinsulinemia and the related GRP78 expression could be a potential therapeutic or preventative target.