Animal studies suggest that increased levels of circulating angiotensin II (AngII) could contribute to the loss of lean body mass in chronic kidney disease, but the mechanism by which this occurs is unclear. Here, AngII infusion increased circulating IL-6 and its hepatic production in wild-type mice, suggesting that AngII-induced inflammation may trigger muscle loss. AngII infusion also stimulated the suppressor of cytokine signaling (SOCS3) in muscle, which led to loss of insulin receptor substrate 1 (IRS-1), thereby impairing insulin/IGF-1 signaling and enhancing protein degradation. All of these responses to AngII were suppressed in IL-6 -deficient mice. Recombinant human IL-6 (rhIL-6) treatment of cultured myotubes only minimally increased SOCS3, however, suggesting the contribution of other mediators. Because AngII increases hepatic serum amyloid A (SAA) expression in an IL-6 -dependent manner, we treated wild-type mice with rhIL-6 and an SAA1-overexpressing adenovirus; the combination led to a significantly greater increase in SOCS3 and decrease in IRS-1 compared with either rhIL-6 or SAA1 alone. We observed similar effects on SOCS3 and IRS-1 when we treated cultured muscle myotubes with rhIL-6 and SAA1. Taken together, these results suggest an interorgan response to high levels of AngII: Hepatic production of IL-6 and SAA increases, and these mediators act synergistically to impair insulin/IGF-1 signaling, which promotes muscle proteolysis. Targeting the high levels of IL-6 and SAA in catabolic disorders might be a therapeutic approach to prevent muscle wasting.

Objective We determined the potential programming effects of maternal obesity and high fat (HF) diet during pregnancy and/or lactation on offspring metabolic syndrome. Study Design A rat model of maternal obesity was created using a HF diet prior to and throughout pregnancy and lactation. At birth, pups were cross fostered thereby generating four paradigms of maternal diets during pregnancy/lactation: (1) control (Con) diet during pregnancy and lactation - Con/Con, (2), HF during pregnancy and lactation - HF/HF, (3) HF during pregnancy alone - HF/Con, and (4) HF during lactation alone - Con/HF. Results Maternal phenotype during pregnancy and the end of lactation evidenced markedly elevated body fat and plasma corticosterone levels in HF dams. In the offspring, maternal HF diet during pregnancy alone programmed increased offspring adiposity, though with normal body weight, whereas maternal HF diet during lactation increased both body weight and adiposity. Metabolic disturbances, particularly that of hyperglycemia, were apparent in all groups exposed to maternal HF diet (during pregnancy and/or lactation), though differences were apparent in the manifestation of insulin resistant versus insulin deficient phenotypes. Elevated systolic blood pressure was manifest in all groups implying that exposure to an obese/HF environment is disadvantageous for offspring health, regardless of pregnancy or lactation periods. Nonetheless, the underlying mechanism may differ as offspring that experienced in utero HF exposure had increased corticosterone levels. Conclusion Maternal obesity/HF diet markedly impact offspring body composition and the risk of metabolic syndrome dependent upon period of exposure during pregnancy and/or lactation.