IL-6 induces lipolysis and mitochondrial dysfunction, but does not affect insulin-mediated glucose transport in 3T3-L1 adipocytes

Abstract

Interleukin-6 (IL-6) has emerged as an important cytokine involved in the regulation of metabolism. However, the role of IL-6 in the etiology of obesity and insulin resistance is not fully understood. Mitochondria are key organelles of energy metabolism, and there is growing evidence that mitochondrial dysfunction plays a crucial role in the pathogenesis of obesity-associated insulin resistance. In this study, we determined the direct effect of IL-6 on lipolysis in adipocytes, and the effects of IL-6 on mitochondrial function were investigated. We found that cells treated with IL-6 displayed fewer lipids and an elevated glycerol release rate. Further, IL-6 treatment led to decreased mitochondrial membrane potential, decreased cellular ATP production, and increased intracellular ROS levels. The mitochondria in IL-6-treated cells became swollen and hollow with reduced or missing cristae. However, insulin-stimulated glucose transport was unaltered. PGC-1α, NRF1, and mtTFA mRNA levels were markedly increased, and the mitochondrial contents were also increased. Our results demonstrate that IL-6 can exert a direct lipolytic effect and induce mitochondrial dysfunction. However, IL-6 did not affect insulin sensitivity in adipocytes in vitro. We deduce that in these cells, enhanced mitochondrial biogenesis might play a compensatory role in glucose transport.

IL-6 regulates adipose deposition and homeostasis in lymphedema

“…This finding is important since it suggests that the degree of lymphatic injury is a critical regulator of IL-6 expression. This hypothesis is supported by previous studies demonstrating that adipose tissues are a major source of circulating IL-6 levels (14,26) and that IL-6 functions as an adipolytic cytokine regulating circulating levels of fatty acids (19,22,23,29,34,36).…”

“…For example, the expression of IL-6 has been shown to correlate with adipose tissue depots in obese patients accounting for as much as 15-30% of circulating IL-6 levels (14,26). Furthermore, recombinant human IL-6 administration has been shown to increase lipolysis and fatty acid oxidation in human subjects as well as in vitro adipose cultures (19,23,29,34). In addition, previous studies have shown that the expression of IL-6 is increased in both primary and surgical models of lymphedema (20,28).…”

Fat in flames: influence of cytokines and pattern recognition receptors on adipocyte lipolysis

“…served across studies (30,56). Also, IL-6-induced lipolysis appears to be influenced by other hormonal factors.…”

Iron primes 3T3-L1 adipocytes to a TLR4-mediated inflammatory response

“…It is possible that early gene expression of TNF-a created a progressive increase in oxidative stress, mitochondrial dysfunction, and lipolysis, which later triggered IL-6 gene to be highly expressed [32]. An important contribution to this mechanism might come even from early IL-6, as recently reported data showed that 3T3-L1 cells treated with 40 mM FeSO 4 and then stimulated with IL-6 further enhanced IL-6 expression, whereas the lowest doses were unable to induce this mechanism [33]. The associated participation of early IL-6 in enhancing lipolysis and mitochondrial dysfunction [34] could contribute to the exacerbation of inflammation by further increasing IL-6 gene expression.…”