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Myokines are emerging as potential mediators of some of the beneficial effects of exercise on the body. Here, Whitham and Febbraio discuss the challenges facing the discovery and validation of myokines and highlight selected myokines with the potential to be therapeutically exploited in cancer and metabolic disease.

In 2012, we were invited by Nature Reviews Endocrinology to write a Review titled ‘Muscles, exercise and obesity: skeletal muscle as a secretory organ’. At the time, following our findings in the 2000s, we knew the concept of skeletal muscle as an endocrine organ was important. Eight years on, the magnitude of the importance of this concept surprises us.

Johnson et al. discuss the role of dietary and endogenous fructose as a calorie source and modulator of metabolic health and disease.

The transcription factors FoxoO1 and Srebp-1 control hepatic glucose and lipid production, respectively. Here, Haeusler et al.propose a model that integrates glucose and lipid regulation in the normal and diabetic liver under the unifying control of FoxO transcription factors.

Cellular metabolic demand skyrockets during intense exercise, thus rendering the communication of metabolic state essential for organismal homeostasis. Murphy, Watt and Febbraio discuss the physiological processes governing intertissue communication during exercise and the molecules mediating such cross-talk.

The chimeric cytokine IC7Fc combines the beneficial effects of the cytokines IL-6 and CNTF on weight loss and metabolism in mice, with no obvious side effects in mice and non-human primates.

Atrial fibrillation and heart failure often coexist but are difficult to treat. Here the authors report a therapeutic strategy for atrial fibrillation and heart failure in mice, based on the activating effect of a small molecule, BGP-15, on IGF1 receptor signalling.

Chronic alcohol use in humans and mice downregulates small intestinal mAChR4 and reduces goblet-cell-associated antigen passage formation, disrupting antimicrobial immunity.

In this Perspective, Murphy and Febbraio reflect on the advances that have been made in the past 20 years in developing therapies for cardiovascular and metabolic diseases that target the immune system. They also consider the potential of emerging immune-based therapies for these diseases.

Obesity and a diet rich in saturated fatty acids can lead to high lipid levels in the liver and insulin resistance. However, inhibition of a key enzyme that elongates long-chain saturated fatty acids can protect against insulin resistance in fatty livers, even with concurrent obesity (pages 1193–1202).

Interleukin 1β (IL-1β) is a cytokine associated with inflammation, obesity and metabolic dysregulation. Surprisingly, IL-1β is also required for maintaining steady-state glucose homeostasis by potentiating postprandial insulin secretion.

The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. A new study now shows that these beneficial effects of adiponectin are dependent on sphingolipid metabolism (pages 55–63).

The authors show that telomere length resetting in embryos, a key determinant of healthy aging, is established by mitochondrial function at conception.

Visceral adipose tissue contains populations of regulatory T cells that exhibit sexual dimorphism, determined by the surrounding niche, and differ between male and female mice in terms of cell number, phenotype, transcriptional landscape and chromatin accessibility.

Although regular physical activity can prevent or reduce the risk of many age-related diseases, the molecular mechanisms underpinning the protective effects of exercise are largely unknown. In 2016, a series of studies demonstrated that crosstalk between tissues during exercise can protect against metabolic disease, cancer, retinal degeneration and memory loss. These studies provide a molecular basis for the concept of 'exercise as medicine'.

The PI3K–PTEN signalling pathway is a central regulator of metabolic homeostasis. Brunner et al. find that cell-intrinsic PI3K signalling allows adipose tissue macrophages to buffer obesity-induced lipotoxicity by promoting lipid uptake and catabolism.

Fructose consumption has greatly increased in recent years and has been linked to the development of hepatic steatosis. Here, the authors show that fructose promotes gut-barrier deterioration and subsequent endotoxaemia that in turn induces hepatic lipogenesis by activation TLR signalling in liver macrophages.

Faecal microbiota transplantation (FMT) has been suggested to be a therapeutic strategy for inflammatory diseases and it is known that regular physical activity can alter the composition of the gut microbiota. Now, a study proposes that FMT might increase exercise performance in athletes, raising the possibility of ‘faecal doping’.

Case reports published over 100 years ago suggested that high-dose sodium salicylate could reduce the symptoms of type 2 diabetes mellitus, but adverse affects precluded clinical use. Now, results from the TINSAL-T2D study that used salsalate, a salicylate prodrug, provide renewed hope for NSAID treatment of type 2 diabetes mellitus.

Skeletal muscle has the capacity to produce, express and release several hundred secreted peptides, so-called myokines. This finding provides a conceptual basis and a new paradigm for understanding the role of skeletal muscle in organ crosstalk, including muscle–liver and muscle–adipose tissue crosstalk. This Review highlights the clinical role of myokines in mediating the multiple health benefits of exercise.

The role of IL-6 in obesity-associated inflammation remains controversial. Bruening and colleagues identify signaling by IL-6 as an important determinant for the alternative activation of macrophages during inflammation.

Clonal expansion of cytotoxic T lymphocytes entails profound energetic demands. Kallies and colleagues show that the transcription factor IRF4 is critical for the metabolic reprogramming, survival and effector function of these cells during clonal expansion.

A key component in the development from fatty liver to hepatocellular carcinoma (HCC) is the appearance of nonalcoholic steatohepatitis (NASH). The precise cellular processes that trigger the advancement of NASH towards HCC are not well understood. In 2018, three key papers were published that help us better understand these processes.

Evidence suggests that physical activity is beneficial for patients with and survivors of cancer. A recent study found that vigorous exercise was associated with reduced mortality in paediatric cancer survivors. Here we discuss these findings in the context of potential mechanisms mediating some of the health effects of exercise in cancer.

Exerkines are signalling moieties that are released in response to acute and/or chronic exercise that exert their effects through endocrine, paracrine and/or autocrine pathways. This Review summarizes the importance and current state of exerkine research, prevailing challenges and future directions.

Increasing the expression of intramuscular heat shock protein 72 preserves muscle strength and ameliorates the dystrophic pathology in two mouse models of muscular dystrophy, suggesting a promising way forward for the treatment of muscular dystrophy.