IL‐6 Contributes to Exercise Induced Recovery of Hepatic Insulin Action in Obese Mice

Obesity is associated with both systemic and hepatic insulin resistance. After only a single bout of exercise, the obesity‐induced impairment in hepatic insulin action is recovered; however, the biological mechanisms that underlie this phenomenon are not known. As circulating levels of interleukin‐6 (IL‐6) are increased after a single bout of exercise, we hypothesized that IL‐6 may contribute to the exercise‐induced recovery of hepatic insulin action in obese mice. To evaluate this hypothesis, we used three experimental approaches. First, C57BL/6 male mice were fed a low fat diet (LFD, 10% kcals from lard) or high fat diet (HFD, 60% kcals from lard) for 7 weeks, which led to increases in body mass, adiposity, and impaired glucose tolerance. Mice from the HFD group were then subjected to a single bout of exercise (2 hours of treadmill exercise at 15 m·min −1 ) or cage control, allowed to recover for 2 hours, and the liver was collected 15 minutes after IP insulin (1 U·kg 1 ). Acute exercise recovered HFD‐induced impairments in insulin‐induced phosphorylation of protein kinase B (AKT) at serine 473 (pAKT Ser473 ), a key insulin signaling protein. This occurred alongside increases in circulating IL‐6 and led to increases in indices of hepatic IL‐6 signaling, including phosphorylation of signal transducer and activator of transcription 3 (pSTAT3) and mRNA expression of suppressor of cytokine signaling 3 (SOCS3). Second, to determine whether IL‐6 was required for the recovery of induced‐insulin pAKT Ser473 with exercise, mice were injected with a neutralizing antibody against IL‐6 (IL‐6 NA) or an IgG control 1 hour prior to exercise. The IL‐6 NA completely ablated exercised‐induced increases in hepatic pSTAT3, which occurred in parallel with an attenuated recovery of pAKT Ser473 , suggesting that IL‐6 contributes to exercise‐induced recovery of hepatic insulin action. Finally, to determine if IL‐6 directly regulates hepatocellular pAKT Ser473 , primary hepatocytes were isolated from lean mice and treated with free fatty acid (FFA: 250 μM oleate, 250 μM palmitate) for 24 hours as a means to increase lipid accumulation and insulin resistance. Cells were then treated with IL‐6 for 90 minutes, including insulin stimulation for the final 15 minutes. IL‐6 induced increases in pSTAT3 protein content were attenuated by FFA treatment. In addition, the FFA‐induced reduction in insulin‐stimulated pAKT Ser473 was not rescued by IL‐6 treatment. Together, this data suggests that the recovery of hepatic insulin action after exercise in obese mice may involve an IL‐6 dependent mechanism; however, the effect of IL‐6 may not be directly in the hepatocytes. Support or Funding Information This work was partially supported by a NSERC grant (341158 to DCW) and a Veterans Affairs VHA‐CDA2 grant (IK2BX001299 to RSR).

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