Focus on cardiometabolic disease

The rise in cardiometabolic diseases is linked to the availability of unhealthy products from industry, such as ultraprocessed foods, and studying the efficacy of intervention strategies against these products must be high on the research agenda.

Dapagliflozin, a sodium-glucose co-transporter-2 inhibitor, reduced the risk of cardiovascular death or heart failure events in 4,744 patients with chronic heart failure with reduced ejection fraction.

Cardiometabolic disease is the leading cause of death and disability in the world, driven in part by the rise in unhealthy diets, poor air quality and other byproducts of economic development. A new economic model is needed, one that places people rather than profits at its center.

Sex differences in the prevalence, risk factors and symptoms of cardiometabolic disorders are being elucidated and should be taken into account in diagnosis and treatment.

The rise of cardiometabolic diseases in low- and middle-income countries is tied to a multitude of environmental, social and commercial determinants, which are discussed in this Review along with a strategy to counteract those factors.

Nonalcoholic fatty liver disease (NAFLD) has emerged as the most prevalent liver disease worldwide, mainly because of the massive parallel global increase in obesity. Extensive public-health and political efforts will be needed in the near future to counteract this disturbing development.

Secreted from adipocytes, adiponectin exerts primarily anti-apoptotic, antiinflammatory, anti-fibrotic and insulin-sensitizing activities on multiple tissues. Here, Straub and Scherer provide a concise overview of the history of adiponectin, its physiological role and molecular mechanism of action.

Systemic homeostasis is finely orchestrated by the action of several organs and molecules. Here Priest et al. provide a comprehensive review that highlights the inter-organ communication complexity in metabolic regulation.

Large-scale sequencing of coding exons of MRAP2 in 9,418 adults and adolescents identifies loss-of-function mutations that are associated with monogenic obesity, hypertension and hyperglycemia.

Targeting the adipokine adipsin and its downstream pathway may provide an approach for preservation of beta cell loss in type 2 diabetes.

Analysis of data from over 400,000 UK Biobank participants shows that eGFR measured by cystatin C, but not serum creatinine, is strongly associated with cardiovascular disease outcomes and mortality.

The beneficial effects of exercise on cardiovascular disease are linked to decreased inflammation through crosstalk between adipose tissue and hematopoietic progenitor cells in the bone marrow.

Single-cell proteomic and transcriptional profiling of atherosclerotic lesions from human carotid arteries reveals specific features of lesional T cells and macrophages associated with symptomatic disease.

Analysis of the UK Biobank reveals new genetic loci associated with estimated visceral adipose tissue (VAT) mass, and suggests that VAT is potentially an independent risk factor for various cardiovascular and metabolic diseases, such as hypertension and type 2 diabetes.

Long-term changes in body weight are determined by rates of adipose lipid turnover.

Chen et al. report that TGF-β signalling, although largely considered anti-inflammatory, has proinflammatory effects on endothelial cells. Inhibition of endothelial TGF-β signalling decreases atherosclerosis in mice and reverts established plaques, in part by decreasing endothelial-to-mesenchymal transitions.

Mechanism-based small-molecule inhibitors targeting a gut microbial enzyme lower circulating levels of the prothrombotic metabolite trimethylamine-N-oxide and suppress diet-induced thrombosis in mice.

Brown adipose tissue (BAT) has high thermogenic potential and is considered a promising target to counteract obesity. Here de Jong et al. demonstrate that human BAT is more similar to classical brown than to beige adipose tissue from mice kept at thermoneutrality and challenged with a high-fat diet.

Creatine can be used for thermogenesis in adipocytes. Here Kazak et al. show that creatine uptake is required to sustain this thermogenic pathway. Knockdown of the creatine transporter, CrT, in adipocytes decreases thermogenesis and energy expenditure, whereas creatine supplementation increases energy expenditure in mice fed a high-fat diet.

m⁶A mRNA methylation regulates several cellular processes, including cancer progression and stem cell maintenance. Here, De Jesus and colleagues demonstrate that the m⁶A landscape segregates human type 2 diabetic islets from controls and that m⁶A is fundamental for human β-cell biology.

The human coronary artery disease gene TCF21 promotes the transformation of smooth muscle cells within atherosclerotic plaques into a newly identified population of fibroblast-like cells that contribute to plaque stability.

A genome-wide association study using electronic health record data in the Million Veteran Program uncovers new genetic loci associated specifically with peripheral artery disease, as compared to stroke or coronary artery disease.

Supplementation with Akkermansia muciniphila, a gut microbe previously associated with metabolic health in preclinical models, is safe and well tolerated in humans and may improve metabolic parameters in overweight and obese patients.

Proinflammatory activation of liver macrophages and their secretion of proinflammatory cytokines have been linked to obesity. Here Morgantini et al. report a mechanism through which liver macrophages can impair liver metabolism and promote insulin resistance in obesity in the absence of an overt proinflammatory phenotype, through secretion of non-inflammatory factors such as IGFBP7.

In a nested case-control study from the China Kadoorie Biobank, lowering blood low-density lipoprotein cholesterol levels confers lower risk for ischemic stroke but elevated risk for intracerebral hemorrhage, which was confirmed by genetic Mendelian randomization analyses.

Maintenance of cholesterol homeostasis is essential to human health. Here, the authors identify and characterize a primate-specific long noncoding RNA, called CHROME, that controls cholesterol homeostasis through fine-tuning of miRNAs and whose levels are elevated in human atherosclerosis.

Metformin decreases the levels of Bacteroides fragilis while increasing the bile acid GUDCA to antagonize intestinal FXR and improves the metabolic health of humans and mice.

Indoleamine 2,3-dioxygenase normally suppresses inflammation, but knockout of its gene is metabolically beneficial as its depletion reshapes the gut microbiota.

A phase 2 placebo-controlled randomized trial reveals that verapamil promotes beta cell function in adult subjects with recent-onset type 1 diabetes.

Post-translational modification of microtubules by detyrosination is prevalent in failing human cardiomyocytes and inhibits cardiomyocyte contraction, suggesting a new therapeutic strategy for improving heart function.

Treatment with setmelanotide, a new-generation MC4R agonist, provides durable weight loss in hyperphagic, leptin receptor–deficient patients, suggesting a pharmacological avenue to treat patients with various MC4R pathway defects.