4-hydroxynonenal causes impairment of human subcutaneous adipogenesis and induction of adipocyte insulin resistance

Objective: Increased adipose production of 4-hydroxynonenal (4-HNE), a bioreactive aldehyde, directly correlates with obesity and insulin resistance. The aim of this study was to elucidate the impact of 4-HNE in mediating adipocyte differentiation and function in two metabolically distinct obese groups; the insulin sensitive (IS) and the insulin resistant (IR). Methods: Subcutaneous (SC) adipose tissues were obtained from eighteen clinically well characterized obese premenopausal women undergoing weight reduction surgery. Cellular distribution of 4-HNE in the form of protein adducts was determined by immunohistochemistry in addition to its effect on oxidative stress, cell growth, adipogenic capacity and insulin signaling in preadipocytes derived from the IS and IR participants. Results: 4-HNE was detected in the SC adipose tissue in different cell types with the highest level detected in adipocytes and blood vessels. Short and long-term in vitro treatment of SC preadipocytes with 4-HNE caused inhibition of their growth and increased production of reactive oxygen species (ROS) and antioxidant enzymes. Repeated 4-HNE treatment led to a greater reduction in the adipogenic capacity of preadipocytes from IS subjects compared to IR and caused dephosphorylation of IRS-1 and p70S6K while activating GSK3a/j3 and BAD, triggering an IR phenotype. Conclusion: These data suggest that 4-HNE-induced oxidative stress plays a role in the regulation of preadipocyte growth, differentiation and insulin signaling and may therefore contribute to adipose tissue metabolic dysfunction associated with insulin resistance.