Circulating interleukin (IL)-18 is elevated in obesity, but paradoxically causes hypophagia. We hypothesized that IL-18 may attenuate high-fat diet (HFD)-induced insulin resistance by activating AMP-activated protein kinase (AMPK). We studied mice with a global deletion of the α-isoform of the IL-18 receptor (IL-18R−/−) fed a standard chow or HFD. We next performed gain-of-function experiments in skeletal muscle, in vitro, ex vivo, and in vivo. We show that IL-18 is implicated in metabolic homeostasis, inflammation, and insulin resistance via mechanisms involving the activation of AMPK in skeletal muscle. IL-18R−/− mice display increased weight gain, ectopic lipid deposition, inflammation, and reduced AMPK signaling in skeletal muscle. Treating myotubes or skeletal muscle strips with IL-18 activated AMPK and increased fat oxidation. Moreover, in vivo electroporation of IL-18 into skeletal muscle activated AMPK and concomitantly inhibited HFD-induced weight gain. In summary, IL-18 enhances AMPK signaling and lipid oxidation in skeletal muscle implicating IL-18 in metabolic homeostasis.

insulin sensitivity was obtained from an oral glucose tolerance test. Body composition was measured by dual-energy X-ray absorptiometry and magnetic resonance imaging. Fat oxidation and energy expenditure were measured during an acute exercise bout of 45 min of ergometer biking at 50% of maximal oxygen consumption (V O2 max). Muscle biopsies from the vastus lateralis of the quadriceps muscle were obtained before and immediately after the exercise bout. Postmenopausal women had 33% [confidence interval (CI) 95%: 12-55] lower whole body fat oxidation (P ϭ 0.005) and 19% (CI 95%: 9 -22) lower energy expenditure (P ϭ 0.02) during exercise, as well as 4.28 kg lower lean body mass (LBM) than premenopausal women. Correction for LBM reduced differences in fat oxidation to 23% (P ϭ 0.05), whereas differences in energy expenditure disappeared (P ϭ 0.22). No differences between groups were found in mRNA [carnitine palmitoyltransferase I, ␤-hydroxyacyl-CoA dehydrogenase (␤-HAD), peroxisome proliferator-activated receptor-␣, citrate synthase (CS), pyruvate dehydrogenase kinase 4, peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣)], protein [phosphorylated AMPactivated protein kinase (AMPK), vascular endothelial growth factor, pyruvate dehydrogenase-1E␣, cytochrome oxidase I], or enzyme activities (␤-HAD, CS) in resting skeletal muscle, except for an increased protein level of cytochrome c in the post-and perimenopausal women relative to premenopausal women. Postmenopausal women demonstrated a trend to a blunted exercise-induced increase in phosphorylation of AMPK compared with premenopausal women (P ϭ 0.06). We conclude that reduced whole body fat oxidation after menopause is associated with reduced LBM. menopause; skeletal muscle; fat oxidation; biopsy MENOPAUSE SIGNALS THE END of the fertile phase of a woman's life and is defined after 12 mo of amenorrhea, as the last menstrual bleeding. At this time point, a marked increase in the incidence of the metabolic syndrome (19, 37), cardiovascular diseases (1, 27, 35), and type 2 diabetes (48) is observed. The increased occurrence of metabolic diseases is likely to be related to changes in body composition, such as an increased amount of body fat (22,29,30,49), changed body fat distribution (22,30,51), and loss of lean body mass (LBM) (12,49,53).Menopause leads to a significant decrease in circulating levels of estrogen as well as increases in gonadotropins. Estrogen seems to influence the substrate choice in humans toward fat oxidation. Hence, fat oxidation is lower in males than in females during endurance exercise (8,17,26,50) and increases in males taking estrogen supplementation (11,16). Furthermore, these gender differences in substrate utilization are only seen when comparing males with females at fertile ages (8,17,26,50). Therefore, it has been hypothesized that reduced estrogen levels with menopause may influence substrate utilization.To our knowledge, only a single previous study has investigated whole body fat oxidation in relation to menopause show...

Aim To investigate markers of systemic inflammation in pre-and postmenopausal women and identify possible predictors of systemic inflammation with menopause. Methods Cross-sectional study of 69 healthy women between 45-and 60 years. Blood samples were collected to assess leukocyte subsets and plasma cytokines. MRI and DXA scans were performed to assess body composition. Through uni-and multivariate analyses, follicle-stimulating hormone (FSH), visceral fat mass and age were evaluated as predictors of systemic inflammation in relation to menopause. Results Postmenopausal women tended to have higher leukocyte counts (5.4 x10 9 vs. 4.9 x10 9 cells/l, p = 0.05) reflected in increased total lymphocytes (1.8 x10 9 vs. 1.6 x10 9 cells/l, p = 0.01) and monocytes (0.5 x10 9 vs. 0.4 x10 9 cells/l, p = 0.02), compared to premenopausal women. Increased visceral fat mass was a strong predictor of high leukocyte subsets. Postmenopausal women had higher plasma TNF-α (2.24 vs. 1.91 pg/ml, p = 0.01) and IL-6 (0.45 vs. 0.33 pg/ml, p = 0.004) compared to premenopausal women and high FSH was a significant predictor of increased plasma TNF-α, IL-1β and IL-6. Menopause was further associated with increased T-cells (1,336 vs. 1,128 cells/μl, p = 0.04) reflected in significantly higher counts of exhausted-, senescent-, and memory CD4+ T-cell subsets. Conclusions Menopause is associated with increased systemic inflammation as well as exhausted-and senescent T-cells. We suggest, that both increased visceral fat mass and declining sex