Jeff M. P. Holly

There has been a global explosion in the prevalence of childhood obesity with 20% of children worldwide now growing up with excess weight and, despite many calls for interventions to redress the costs to health and society, rates continue to rise. It has also recently been observed that there is a global trend with the incidence of early-onset cancers, diagnoses prior to age 50, increasing. We outline the different lines of evidence implicating that these two trends may be linked. Conclusive proof will only be obtained when longitudinal studies, initiated after the current surge in childhood obesity, mature. This will require decades, however, due to the long time-lag between exposure and cancer presentation it would then be too late to avoid a time-bomb of early cancers. This adds considerable urgency to the calls for more effective action to prevent the current epidemic of childhood obesity. The obesity epidemic is driven by an obesogenic food system to which children are particularly vulnerable. Protecting children will require broad multisector coalitions to enable sets of mutually reinforcing policies such as front-of-pack food labelling, restrictions on the ubiquitous marketing, food taxes, subsidies and mandated healthy school meal programs.

The global obesity crisis involves an unprecedented and rapid change to the human phenotype. Conferring vast levels of avoidable morbidity and mortality at enormous cost, it has proved refractory to previous policy-led action. This article reviews recent developments in our understanding of obesity and its links to the climate co-crisis, aiming to inform evidence-based, societal-level actions to address both. Recent therapeutic developments now offer transformative interventions for millions of people living with obesity. However, treating all affected adults and children with major bariatric surgery or lifelong anti-obesity medication is unsustainable given the risks and costs. The obesity crisis has been driven primarily by the transformation of our food environment toward diets dominated by ultra-processed foods (UPFs) that exert multiple addictive and obesogenic mechanisms. Emerging evidence shows that not all UPFs have the same impact: processed meat and low-fiber, energy-dense UPFs are linked with poorer outcomes compared with less energy-dense, high-fiber, plant-rich UPFs, indicating that more nuanced classifications would be helpful. This food system also contributes significantly to climate change and other environmental harms, primarily through ruminant meat consumption. Both climate change and obesity are driven by unsustainable, but profitable, consumption. Solutions exist but have not been adequately implemented owing to a lack of political will. They require food system reforms that replace energy-dense UPFs with unprocessed foods and reduce animal-sourced foods. Accumulating evidence supports prioritizing actions to remove market distortions via increasing cost transparency, taxing unhealthy foods (redirecting the proceeds to public health), combating marketing, effective food labeling, facilitating healthy food choices, promoting healthy living environments, and public and professional education. New economic models, market demand shifts, and technological innovation should all be harnessed to overcome economic and political barriers, and food system reform should be integral to future actions to achieve the Sustainable Development Goals. This transformation to improve both human and planetary health will require interdisciplinary scientific advocacy and coalition-building across society. During the COVID-19 pandemic, societies recognized how rapid, concerted, science-led action can effectively address a global threat; a similar societal shift is required to motivate the political action needed to address the obesity crisis.

The prevalence of obesity and type 2 diabetes mellitus (T2DM) have grown alarmingly across the world during the last few decades and have become major challenges for public health. Both conditions present due to hormonal disturbances, and it has become increasingly clear that these result from dietary changes caused by a transformation in our food environment. Anjom-Shoae et al. review recent evidence examining the acute and long-term effects of high protein diets and comparing the effects of diets high in either animal or plant proteins (2). It is well established that high protein diets can have beneficial effects on body weight and glycaemic control, at least over a short timeframe, related to their effects on satiety, gastric emptying times and gut hormone release. Diets high in either animal or plant proteins had these beneficial effects on body weight and glycaemic control over shorter periods; in comparison, longer-term studies, greater than 12 months, indicated that diets high in plant proteins had either neutral or beneficial effects, whereas diets high in animal protein exerted adverse effects. The latter observations are consistent with several prospective epidemiological studies of large populations that have all shown that diets high in animal proteins are associated with an increased risk of obesity and T2DM. The reasons for the differential long-term effects of animal and plant proteins are not clear, but could be due to differences in amino acid composition, glycaemic load and/or the higher insulinotropic effects of animal proteins, with the insulin then promoting fat deposition and inhibiting fat oxidation. More studies are needed to understand the effects of different proteins on the gastrointestinal and other mechanisms involved in food intake and glycaemic control.With the prevalence of T2DM continuing to grow, the marked differences in its presentation and progression present challenges for the management of patients. Groups working with the Risk Assessment and Progression of Diabetes (RHAPSODY) consortium have used an unsupervised, "bottom-up", multimodal, multivariate strategy to analyze multi-omic data obtained from two European cohorts of patients with T2DM in order to better characterize the complexity of the molecular interactions that underlie this heterogeneity among patients (3). By measuring 180 circulating lipids and 1195 proteins, they identified two subgroups of patients who differed in terms of insulin sensitivity and secretion, and glycemic deterioration,. and identified various groups of biomarkers, most notably those involved in immune processes, that were associated with these distinct subgroups of patients. These biomarkers will provide valuable targets for future studies examining causal pathways for disease progression.Proinflammatory cytokines have been implicated in the pancreatic -cell failure that underlies both type 1 diabetes mellitus (T1DM) and T2DM. Understanding the molecular mechanisms in this process can lead to the discovery of biomarkers that may assist in monitoring disease progression and to new targets for therapeutic interventions. A novel cytokine mediated effect on -cell RNA turnover is reported by Ghjiasi et al (4). Another very international collaboration used human and rodent -cell models to reveal a novel cytokine mediated effect on -cell RNA turnover. These investigators found that cytokines decreased the activity of nonsense-mediated RNA decay (NMD), which normally functions to eliminate premature termination containing mRNAs, and thus could disturb the balance between anti-and pro-apoptotic transcripts. These findings open up new avenues of research into the various components of the NMD machinery as potential biomarkers or therapeutic targets.The regulation of reproductive function is intimately controlled in relation to metabolic status. Recent advances in our understanding of the pathways involved is reviewed by Rodríguez-Vázquez et al, with a focus on the impact of metabolism on pubertal development and fertility (5). They describe the pivotal role played by the hypothalamus in integrating central neuronal signals with hormonal signals, wherein peripheral metabolic hormones such as leptin, insulin, and ghrelin act on Kiss1 and GnRH neurons to regulate pubertal development according to metabolic status. In addition, it has emerged that many cellular sensors also play a direct role in this integration, including energy sensors such as AMPK, mTOR and SIRT1, as well as several lipid sensing pathways, including fatty acid receptors, fatty acid transport proteins, and nuclear receptors. Nuclear receptors such as peroxisome proliferator-activated receptors are differentially expressed in specific hypothalamic neurons, and when fatty acids are bound, these are then translocated to the nucleus where they can activate or repress gene transcription. In addition, both bile acids (BA), which are synthesised in the liver, and secondary BA, which are formed after transformation by the gut microbiota, interact with the G protein coupled-receptor, TGR5, in the hypothalamus. A complex framework for the integral regulation of whole-body metabolism and reproductive function is described, which should enable further functional connectivity mapping of the hypothalamic neuronal and glial cells involved.Cushing's syndrome (CS) is a classical, but relatively rare, endocrine disease that is due to hypercortisolism and is treated by surgical excision of the causal adrenal or pituitary lesion. Despite successful treatment a large proportion of patients in remission suffer from persistent fatigue, muscle weakness and sarcopenia. Recent evidence has increasingly implicated microRNAs (miRNAs) in skeletal muscle regulation and Seco-Cervera et al. conducted a pilot study screening for circulating miRNAs that could be potential biomarkers of sarcopenia in a group of patients with CS in sustained...

The role if insulin-like growth factor binding protein-2 (IGFBP-2) in mediating chemoresistance in breast cancer cells has been demonstrated, but the mechanism of action is unclear. This study aimed to further investigate the role of IGFBP-2 in the DNA damage response induced by etoposide in MCF-7, T47D (ER+ve), and MDA-MB-231 (ER-ve) breast cancer cell lines. In the presence or absence of etoposide, IGFBP-2 was silenced using siRNA in the ER-positive cell lines, or exogenous IGFBP-2 was added to the ER-negative MDA-MB-231 cells. Cell number and death were assessed using trypan blue dye exclusion assay, changes in abundance of proteins were monitored using Western blotting of whole cell lysates, and localization and abundance were determined using immunofluorescence and cell fractionation. Results from ER-positive cell lines demonstrated that upon exposure to etoposide, loss of IGFBP-2 enhanced cell death, and this was associated with a reduction in P-DNA-PKcs and an increase in γH2AX. Conversely, with ER-negative cells, the addition of IGFBP-2 in the presence of etoposide resulted in cell survival, an increase in P-DNA-PKcs, and a reduction in γH2AX. In summary, IGFBP-2 is a survival factor for breast cancer cells that is associated with enhancement of the DNA repair mechanism.

Supplementary Fig. S1. Effect by caffeine or caffeic acid on apoptotic mediators