NEW INVESTIGATOR AWARD FINALISTS NIA0001 Induction of differentiation in human preadipocytes may contribute to adipogenic effect of human adenovirus Ad‐36

Abstract

Human adenovirus Ad‐36 causes adiposity in animal models and shows association with human obesity. The mechanism involved is unknown. We previously reported that Ad‐36 enhances differentiation of 3T3‐L1 preadipocytes and E4orf‐1 gene of the virus is responsible for the adipogenic effect in the rodent cell line. We undertook a three‐step approach to investigate the role of preadipocyte differentiation in adipogenic effect of Ad‐36. First, we showed that the viral mRNA is expressed in adipose‐derived stem cells (ASC) of animals experimentally infected with Ad‐36. Infection of rats with Ad‐36 resulted in increased epididymal fat pad weight and the expression of Ad‐36 E4orf‐1 mRNA was detected in ASC isolated from the fat pads. Next, we determined if humans naturally infected with Ad‐36 will show greater preadipocyte differentiation. Subcutaneous adipose‐tissue samples from 33 Pima Indian subjects were screened by nested‐PCR specific for Ad‐36 DNA. Nine subjects (27%) had Ad‐36 DNA. A blinded comparison of their ASC showed greater differentiation to adipocytes for the Ad‐36 DNA positive subjects (P = 0.06) compared to the Ad‐36 DNA negative group. Finally, we used a direct approach. Human‐ASC when infected with Ad‐36 showed spontaneous replication, differentiation, and lipid accumulation, which was significantly greater than the uninfected controls (P < 0.01). Ad‐36 induced lipid accumulation in human‐ASC increased in response to the viral load and the lipogenic response was observed regardless of the donor gender and over an age range of 22–57 years. These results suggest that ability of Ad‐36 to induce preadipocyte differentiation may play a role in human adiposity.