Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-alpha, which is reflected by elevated levels of soluble TNF-alpha receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-alpha rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-alpha. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-alpha and thereby offers protection against TNF-alpha-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases.

Aims/hypothesis Decreased levels of brain-derived neurotrophic factor (BDNF) have been implicated in the pathogenesis of Alzheimer's disease and depression. These disorders are associated with type 2 diabetes, and animal models suggest that BDNF plays a role in insulin resistance. We therefore explored whether BDNF plays a role in human glucose metabolism. Subjects and methods We included (Study 1) 233 humans divided into four groups depending on presence or absence of type 2 diabetes and presence or absence of obesity; and (Study 2) seven healthy volunteers who underwent both a hyperglycaemic and a hyperinsulinaemic-euglycaemic clamp.Results Plasma levels of BDNF in Study 1 were decreased in humans with type 2 diabetes independently of obesity. Plasma BDNF was inversely associated with fasting plasma glucose, but not with insulin. No association was found between the BDNF G196A (Val66Met) polymorphism and diabetes or obesity. In Study 2 an output of BDNF from the human brain was detected at basal conditions. This output was inhibited when blood glucose levels were elevated. In contrast, when plasma insulin was increased while maintaining normal blood glucose, the cerebral output of BDNF was not inhibited, indicating that high levels of glucose, but not insulin, inhibit the output of BDNF from the human brain. Conclusions/interpretation Low levels of BDNF accompany impaired glucose metabolism. Decreased BDNF may be a pathogenetic factor involved not only in dementia and depression, but also in type 2 diabetes, potentially explaining the clustering of these conditions in epidemiological studies.

Our results indicate that IL-15 may be a regulator of trunk fat mass.

Smoking causes multiple organ dysfunction. The effect of smoking on skeletal muscle protein metabolism is unknown. We hypothesized that the rate of skeletal muscle protein synthesis is depressed in smokers compared with non-smokers. We studied eight smokers (Ն20 cigarettes/day for Ն20 years) and eight non-smokers matched for sex (4 men and 4 women per group), age (65 Ϯ 3 and 63 Ϯ 3 yr, respectively; means Ϯ SEM) and body mass index (25.9 Ϯ 0.9 and 25.1 Ϯ 1.2 kg/m 2 , respectively). Each subject underwent an intravenous infusion of stable isotope-labeled leucine in conjunction with blood and muscle tissue sampling to measure the mixed muscle protein fractional synthesis rate (FSR) and whole body leucine rate of appearance (Ra) in plasma (an index of whole body proteolysis), the expression of genes involved in the regulation of muscle mass (myostatin, a muscle growth inhibitor, and MAFBx and MuRF-1, which encode E3 ubiquitin ligases in the proteasome proteolytic pathway) and that for the inflammatory cytokine TNF-␣ in muscle, and the concentration of inflammatory markers in plasma (C-reactive protein, TNF-␣, interleukin-6) which are associated with muscle wasting in other conditions. There were no differences between nonsmokers and smokers in plasma leucine concentration, leucine rate of appearance, and plasma concentrations of inflammatory markers, or TNF-␣ mRNA in muscle, but muscle protein FSR was much less (0.037 Ϯ 0.005 vs. 0.059 Ϯ 0.005%/h, respectively, P ϭ 0.004), and myostatin and MAFBx (but not MuRF-1) expression were much greater (by ϳ33 and 45%, respectivley, P Ͻ 0.05) in the muscle of smokers than of nonsmokers. We conclude that smoking impairs the muscle protein synthesis process and increases the expression of genes associated with impaired muscle maintenance; smoking therefore likely increases the risk of sarcopenia. muscle growth; stable-isotope-labeled tracers; sarcopenia; protein turnover ALTHOUGH THE NUMBER OF SMOKERS has declined steadily over the past 50 years, ϳ20% of US adults still smoke regularly (3, 6). One-third of these are "heavy smokers," consuming 20 or more cigarettes daily (6). The prevalence of habitual tobacco consumption is even greater in Great Britain (6) and throughout Europe (17), as well as in the developing world (17).Tobacco use poses a major public health problem because smoking is a major risk factor for cardiovascular disease, chronic obstructive pulmonary disease, and lung cancer (43, 57) and is associated with increased risk for other debilitating conditions, such as cataract, pneumonia, and cancers of the cervix, kidney, pancreas, and stomach (1). There is also some evidence that smoking may impair physical function (33) and probably increases the risk for sarcopenia (i.e., age-related muscle wasting) (2, 45). This suggests that smoking has direct adverse effects on muscle protein metabolism, which may lead to loss of independence and disability with advanced age. Nevertheless, the effect of smoking on muscle protein metabolism is not known.A number of conditions i...