Adipocyte-specific gp130 signalling mediates exercise-induced weight reduction.

BACKGROUND: Repetitive physical activity is a well-established intervention to reduce obesity and to prevent weight regain. Besides increased energy expenditure, reduced caloric intake may contribute to exercise-induced weight loss in obesity. Using adipocyte-specific glycoprotein 130 knockout (gp130Δadipo) mice, we recently unravelled that obesity-induced interleukin-6 (IL-6) signalling in adipose tissue contributes to circulating levels of the two anorectic hormones leptin and insulin. Herein, we aimed to investigate the role of adipocyte-specific IL-6 signalling in exercise-mediated appetite control and, hence, weight reduction in obesity. METHODS: gp130Δadipo and control littermate mice (gp130F/F) were repetitively exercised during a 12-week period of HFD-feeding. Thermogenesis was determined using thermography and food intake as well as energy expenditure were assessed in metabolic cages. Circulating IL-6, insulin and leptin levels were measured using immunoassays. Protein levels of phosphorylated STAT3, JAK2 and Akt were determined in the hypothalamus by Western blot technique. RESULTS: Repetitive physical activity reduced food intake and HFD-induced weight gain in gp130F/F but not gp130Δadipo mice. In contrast, energy expenditure was not different between the genotypes. Circulating insulin and leptin levels were significantly reduced in gp130Δadipo mice. Moreover, hypothalamic leptin and insulin signalling were enhanced in exercised gp130F/F but not gp130Δadipo mice as demonstrated by elevated pSTAT3, pJAK2 and pAkt protein levels. CONCLUSION: Adipocyte-specific IL-6 signalling is involved in exercise-mediated regulation of food intake and weight reduction in HFD-fed mice.

Oncostatin M suppresses browning of white adipocytes via gp130-STAT3 signaling.

OBJECTIVE: Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state. METHODS: Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively. RESULTS: Inguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = -0.413, p < 0.001, n = 66). CONCLUSIONS: Our data support the notion that OSM negatively regulates thermogenesis in WAT and thus may be an attractive target for treating obesity.