Role of physiological levels of 4-hydroxynonenal on adipocyte biology: implications for obesity and metabolic syndrome

Abstract

Lipid peroxidation products such as 4-hydroxynonenal (HNE) are known to be increased in response to oxidative stress, and are known to cause dysfunction and pathology in a variety of tissues during periods of oxidative stress. The aim of the current study was to determine the chronic (repeated HNE exposure) and acute effects of physiological concentrations of HNE towards multiple aspects of adipocyte biology using differentiated 3T3-L1 adipocytes. Our studies demonstrate that acute and repeated exposure of adipocytes with physiological low concentrations of HNE is sufficient to promote subsequent oxidative stress, impaired adipogenesis, alter the expression of adipokines, and increase lipolytic gene expression and increase FFA release. These results provide an insight in to the role of HNE induced oxidative stress in regulation of adipocyte differentiation and adipose dysfunction. Taken together, these data indicate a potential role for HNE promoting diverse effects towards adipocyte homeostasis and adipocyte differentiation, which may be important to the pathogenesis observed in obesity and metabolic syndrome.

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

“…The increased catalase activity in 4-HNE treated differentiating preadipocytes was more significant in IS-derived cells, suggesting higher sensitivity to 4-HNE-induced oxidative stress, compared to IR-derived counterparts. Taken together, our data confirm both earlier in vitro findings of increased ROS production in response to 4-HNE in 3T3L-1 preadipocyte cell line [26] and in vivo observations of elevated ROS scavenging enzymes in adipose tissues from obese subjects with increased 4-HNE levels [17], adding to the significant role 4-HNE plays in modulating adipose tissue homeostasis.…”

“…Therefore physiological levels of 4-HNE (up to 10 µM) in adipose tissues play a crucial role in redox homeostasis, whereas elevated 4-HNE levels (above 10 µM) can cause adipocyte dysfunction and insulin resistance [26,39]. This study reports for the first time Emerging data initially showed that elevated levels of 4-HNE in SC adipose tissues are located mainly within adipocytes and blood vessels in comparable levels between IS and IR subjects.…”

“…The data indicated that acute 4-HNE treatment of preadipocytes at a concentration that is at the lower end of the pathophysiological range [15], and reported previously in 3T3L-1 preadipocytes [26], increases intracellular hydrogen peroxide as well as ROS production in preadipocytes in a concentration-dependent manner, which is also associated with increased levels of ROS scavenging enzymes including catalase, PRX2, TRX1, SOD1…”

“…The role of 4-HNE on impairment of adipocyte differentiation was shown in 3T3L1 murine preadipocytes, where short-term as well as repeated exposure of these cells to physiological concentrations of 4-HNE promoted subsequent oxidative stress, impaired adipogenesis, alteration of the expression of adipokines, increased lipolytic gene expression and free fatty acids release [26]. These effects were suggested more recently to be mediated by a decrease in aldehyde dehydrogenase 2 activity [27].…”

Aldehyde dehydrogenase 1 a1 regulates energy metabolism in adipocytes from different species

“…Rald has been shown to inhibit PPARγ activation . Hydroxynonenal is another ALDH1A1 substrate (low affinity), which can also inhibit lipid accumulation . Thus, ALDH1A1 function suggests a lipid‐dependent mechanism for regulation of energy homeostasis in xenocultures.…”