PPARγ-Independent Increase in Glucose Uptake and Adiponectin Abundance in Fat Cells

Although thiazolidinediones (TZD) effectively improve hyperglycemia and increase adiponectin, a proinsulin-sensitizing adipokine, they also increase adipogenesis via peroxisome proliferator-activated receptor (PPAR)gamma induction, which may be undesirable. Recent safety concerns about some TZD have prompted the search for next generation agents that can enhance glycemic control and adiponectin independent of PPAR gamma or adipogenesis. Reminiscent of TZD action, a human adenovirus, adenovirus 36 (Ad36), up-regulates PPAR gamma, induces adipogenesis, and improves systemic glycemic control in vivo. We determined whether this effect of Ad36 requires PPAR gamma and/or adipogenesis. Glucose uptake and relevant cell signaling were determined in mock-infected orhuman adenoviruses Ad36 or Ad2-infected cell types under the following conditions: 1) undifferentiated human-adipose-tissue-derived stem cells (hASC), 2) hASC differentiated as adipocytes, 3) hASC in presence or absence of a PPAR gamma inhibitor, 4) NIH/3T3 that have impaired PPAR gamma expression, and 5) PPAR gamma-knockout mouse embryonic fibroblasts. Mouse embryonic fibroblasts with intact PPAR gamma served as a positive control. Additionally, to determine natural Ad36 infection, human sera were screened for Ad36 antibodies. In undifferentiated or differentiated hASC, or despite the inhibition, down-regulation, or the absence of PPAR gamma, Ad36 significantly enhanced glucose uptake and PPAR gamma, adiponectin, glucose transporter 4, and glucose transporter 1 protein abundance, compared with mock or Ad2-infected cells. This indicated that Ad36 up-regulates glucose uptake and adiponectin secretion independent of adipogenesis or without recruiting PPAR gamma. In humans, natural Ad36 infection predicted greater adiponectin levels, suggesting a human relevance of these effects. In conclusion, Ad36 provides a novel template to metabolically remodel human adipose tissue to enhance glycemic control without the concomitant increase in adiposity or PPAR gamma induction associated with TZD actions. (Endocrinology 152: 3648-3660, 2011)