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Increasing mitochondrial oxidative capacity and energy expenditure holds therapeutic potential for obesity and metabolic disorders. Here, the authors identify MTCH2 as a mitochondrial regulator of fatty acid oxidation via interaction with CPT1.

A post hoc analysis of a multicentre, randomised trial showed that prediabetes remission is possible without total weight loss—providing weight is distributed to subcutaneous deposits as opposed to visceral ones.

Adipose tissue (AT) inflammation is strongly associated with obesity and constitutes an obesogenic memory upon weight loss. Here, the authors show that intermittent fasting leads to an adipocyte p53-signaling dependent emergence of lipid-associated macrophages in visceral AT of obese mice which limits the systemic fasting response.

Coordinated hormonal interactions in response to feeding and fasting regulate glucose homeostasis. Here the authors report that Activin B, expressed in the liver sinusoidal endothelial cells, is involved in glucose homeostasis by regulating hepatic FGF21 production and glucagon sensitivity and can be inhibited by adipocyte-derived FSTL3 during obesity.

Over the past 20 years, obesity research has resulted in a better understanding of the complex disease mechanisms underlying the condition, including biological, behavioural, societal and environmental factors. Although obesity research in the past 10 years has resulted in very effective and safe obesity treatments, more research is needed to improve the lives of people with obesity.

A transancestral exome-wide association study for body-fat distribution identifies protein-coding variants that are significantly associated with waist-to-hip ratio adjusted for body mass index.

Exome-wide analysis identifies rare and low-frequency coding variants associated with body mass index. Gene-based meta-analysis and functional studies implicate 13 genes, eight of which are novel, and neuronal pathways as factors in human obesity.

Trans-ethnic analyses of exome array data identify new risk loci for type 2 diabetes. Fine-mapping analyses using genome-wide association data show that the index coding variants represent the likely causal variants at only a subset of these loci.

Timothy Frayling, Joel Hirschhorn, Peter Visscher and colleagues report a meta-analysis of genome-wide association studies for adult height in 253,288 individuals. They identify 697 variants in 423 loci significantly associated with adult height and find that these variants cluster in pathways involved in growth and together explain one-fifth of the heritability for this trait.

Simultaneous PET-MRI measurements provide fundamental insights into the modulation of neural networks mediated by nicotinic acetylcholine receptors in human obesity as a putative biological mechanism for future weight loss interventions.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

The concept of metabolically healthy obesity (MHO) suggests that obesity might be a benign condition. This view has been challenged by a recent study demonstrating that, among 3.5 million individuals, those with MHO still have a higher risk of cardiovascular diseases than individuals who are metabolically healthy and normal weight.

A trans-ancestry meta-analysis of GWAS of glycemic traits in up to 281,416 individuals identifies 99 novel loci, of which one quarter was found due to the multi-ancestry approach, which also improves fine-mapping of credible variant sets.

The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.

Data from over 700,000 individuals reveal the identity of 83 sequence variants that affect human height, implicating new candidate genes and pathways as being involved in growth.

Oxidized lipids are prominent bioactive agents, and yet their molecular repertoire remains largely unknown. Here, the authors apply bioinformatics and LC-MS/MS to uncover the diversity and specificity of modified lipids in human blood plasma of lean and obese individuals.

Single-nucleus RNA sequencing of human visceral and subcutaneous adipose tissues is used to identify adipocyte subpopulations and explore their developmental trajectories and interactions.

N6 - methyladenosine (m6 A) is a prevalent and abundant mRNA modification, yet its cell-type specific roles remains unclear. Here, the authors show that m6 A modification differentially regulates the transcriptomes of brown and white adipose tissue, resulting in distinct impacts on systemic metabolism.

Genome-wide association meta-analyses of waist-to-hip ratio adjusted for body mass index in more than 224,000 individuals identify 49 loci, 33 of which are new and many showing significant sexual dimorphism with a stronger effect in women; pathway analyses implicate adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution.

Brown and beige adipose tissues contribute to organismal energy expenditure by generating heat. Here, Klepac et al. survey G protein-coupled receptors in brown fat and show that G_q-coupled receptors inhibit expression of thermogenic proteins in mice and in human adipocytes.

Stable epigenetic changes indicate the existence of an obesogenic memory in mouse adipocytes that primes cells for pathological responses in an obesogenic environment and potentially contributes to the problematic ‘yo-yo’ effect often seen with dieting.

Calorie burning is normally turned off in thermogenic brown fat at warm temperatures. Here the authors show that adipocyte oxygen sensing directly boosts brown fat calorie burning, even at warm temperatures.

Non-alcoholic steatohepatitis (NASH) is characterized by lipid accumulation within hepatocytes and fibrosis. Seitz et al. show that the GTPase protein Rab24 is increased in the livers of people who are obese or have NASH.

Kyle Gaulton, Mark McCarthy, Andrew Morris and colleagues report fine mapping and genomic annotation of 39 established type 2 diabetes susceptibility loci. They find that the set of potential causal variants is enriched for overlap with FOXA2 binding sites in human islet and liver cells, and they show that a likely causal variant near MTNR1B increases FOXA2-bound enhancer activity, providing a molecular mechanism to explain the effect of this locus on disease risk.

In this Review, the authors present a roadmap towards achieving consensus on development, analysis and interpretation of single-cell transcriptomics data in adipose tissue, including discussion of roadblocks, best practices and ideal cell-type markers for annotation of adipose tissue cell types in mice and humans.

Secreted isoform of endoplasmic reticulum membrane complex subunit 10 (scEMC10) is a secreted protein of incompletely understood physiological function. Here the authors show that scEMC10 is upregulated in people with obesity, and that that genetic EMC10 deletion or antibody-based neutralization of EMC10 prevents diet-induced obesity in mice.

Single-cell studies of human white adipose tissue (WAT) provide insights into the specialized cell types in the tissue. Here the authors combine publicly available and newly generated high-resolution and bulk transcriptomic results from multiple human datasets to provide a comprehensive cellular map of white adipose tissue.

Untargeted metabolomics demonstrate that apoptotic brown adipocytes release a specific pattern of metabolites with purine metabolites being highly enriched, and inosine is identified as a metabolite released during apoptosis regulating thermogenic fat and counteracting obesity.

The brown fat-derived neuregulin 4 regulates hepatic lipid homeostasis and whole-body insulin sensitivity

TMAO is known to be atherothrombotic. Here the authors show that i) kidney function is the main determinant of serum TMAO, ii) TMAO increases kidney scarring with TGF-β1 signalling and iii) anti-diabetic drugs with reno-protective properties such as GLP1R agonists reduce plasma TMAO.

Bondareva and Rodríguez-Aguilera et al. use scRNA-seq to analyze transcriptomes of 375,000 endothelial cells from seven organs in male mice at various stages of obesity to identify organ-specific vulnerabilities.

A mutation leading to ubiquitous ectopic expression of agouti signaling protein, which is not picked up in conventional genetic screenings, is reported in patients with severe childhood obesity.

Obesity and a high-fat diet can lead to insulin resistance in a process involving macrophage-mediated inflammation of adipose tissue. Here the authors show that glucocorticoid receptor-deficient macrophages have an elevated inflammatory response which aggravates insulin resistance implicating that glucocorticoids promote insulin-sensitizing actions via adipose tissue macrophages during obesity.

A genome-wide association meta-analysis study here shows novel genetic loci to be associated to body fat percentage, and describes cross-phenotype association that further demonstrate a close relationship between adiposity and cardiovascular disease risk.

A genome-wide association study and Metabochip meta-analysis of body mass index (BMI) detects 97 BMI-associated loci, of which 56 were novel, and many loci have effects on other metabolic phenotypes; pathway analyses implicate the central nervous system in obesity susceptibility and new pathways such as those related to synaptic function, energy metabolism, lipid biology and adipogenesis.

Past genome-wide associate studies have identified hundreds of genetic loci that influence body size and shape when examined one trait at a time. Here, Jeff and colleagues develop an aggregate score of various body traits, and use meta-analysis to find new loci linked to body shape.

Dong and Sun et al. show that adipogenesis regulatory cells in murine white adipose tissue inhibit adipogenesis through RSPO2, which regulates maturation of early progenitor cells via Lgr4.

Baboota et al. investigate senescence as a driver of human NAFLD/NASH and show the roles of BMP4 and its antagonist Gremlin 1 as anti-senescent and pro-senescent molecules, respectively.

Elevated hepatic alanine catabolism is shown to promote hyperglycaemia and reduce skeletal muscle protein synthesis, thereby linking sarcopenia with hyperglycaemia in the context of type 2 diabetes.

Uncoupling protein-1 (UCP1) plays a central role in energy dissipation in brown adipose tissue. Here the authors show that FGF6 and FGF9 induce UCP1 expression in adipocytes and preadipocytes, via modulation of a transcriptional network that is dissociated from brown adipogenesis.

Downregulation of the glucose transporter GLUT4 in adipose tissue occurs early in the development of type 2 diabetes; here GLUT4-mediated glucose uptake is shown to induce a novel form of the transcription factor ChREBP, which regulates de novo lipogenesis and systemic glucose metabolism.