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Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity
A large-scale epigenome-wide association study identifies changes in DNA methylation associated with body mass index in blood and adipose tissue, and correlates DNA methylation sites with high risk of incident type 2 diabetes.
Body fat and diabetes risk
Obesity is a major risk factor for type 2 diabetes and related metabolic disorders. Genetic association studies have identified genomic loci associated with obesity, and recent studies have also suggested associations with DNA methylation. These authors report an epigenome-wide association study for body mass index (BMI), identifying an association with DNA methylation at 187 loci in blood and adipose tissue. They find that these methylation changes are secondary to adiposity and are also associated with an increased risk of developing type 2 diabetes, independent of conventional risk factors.
Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances
1
,
2
. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation
3
,
4
,
5
,
6
, a key regulator of gene expression and molecular phenotype
7
. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with
P
< 1 × 10
−7
, range
P
= 9.2 × 10
−8
to 6.0 × 10
−46
;
n
= 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (
P
< 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (
P
< 9.0 × 10
−6
, range
P
= 5.5 × 10
−6
to 6.1 × 10
−35
,
n
= 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07–2.56);
P
= 1.1 × 10
−54
). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.
Journal Article
Fatboy fall down
\"A heartrending novel about one man's search for meaning in a difficult life. A child ridiculed for his weight, a son overshadowed by a favored brother, a husband who falls short of his wife's ambitions, an old man with a broken heart... As Orbits's life passes, he doggedly pursues a simple dream--a little place in the country where a family might thrive--while wondering if he can ever shake free of the tragedies that seem to define him. Fatboy fall down is the lush and heartbreaking musings of a man trying to understand his place in the world. Though it's a story shot through with sadness, it speaks to universal truths, and Rabindranath Maharaj's deft touch underscores the resilience of the human spirit\"-- Provided by publisher.
Book
Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study
Metabolic syndrome is characterized by a constellation of comorbidities that predispose individuals to an increased risk of developing cardiovascular pathologies as well as type 2 diabetes mellitus1. The gut microbiota is a new key contributor involved in the onset of obesity-related disorders2. In humans, studies have provided evidence for a negative correlation between Akkermansia muciniphila abundance and overweight, obesity, untreated type 2 diabetes mellitus or hypertension3–8. Since the administration of A. muciniphila has never been investigated in humans, we conducted a randomized, double-blind, placebo-controlled pilot study in overweight/obese insulin-resistant volunteers; 40 were enrolled and 32 completed the trial. The primary end points were safety, tolerability and metabolic parameters (that is, insulin resistance, circulating lipids, visceral adiposity and body mass). Secondary outcomes were gut barrier function (that is, plasma lipopolysaccharides) and gut microbiota composition. In this single-center study, we demonstrated that daily oral supplementation of 1010A. muciniphila bacteria either live or pasteurized for three months was safe and well tolerated. Compared to placebo, pasteurized A. muciniphila improved insulin sensitivity (+28.62 ± 7.02%, P = 0.002), and reduced insulinemia (−34.08 ± 7.12%, P = 0.006) and plasma total cholesterol (−8.68 ± 2.38%, P = 0.02). Pasteurized A. muciniphila supplementation slightly decreased body weight (−2.27 ± 0.92 kg, P = 0.091) compared to the placebo group, and fat mass (−1.37 ± 0.82 kg, P = 0.092) and hip circumference (−2.63 ± 1.14 cm, P = 0.091) compared to baseline. After three months of supplementation, A. muciniphila reduced the levels of the relevant blood markers for liver dysfunction and inflammation while the overall gut microbiome structure was unaffected. In conclusion, this proof-of-concept study (clinical trial no. NCT02637115) shows that the intervention was safe and well tolerated and that supplementation with A. muciniphila improves several metabolic parameters.
Journal Article
Fat Rights
Author Interview on The Brian Lehrer Show America is a
weight-obsessed nation. Over the last decade, there's been an
explosion of concern in the U.S. about people getting fatter.
Plaintiffs are now filing lawsuits arguing that discrimination
against fat people should be illegal. Fat Rights
asks the first provocative questions that need to be raised about
adding weight to lists of currently protected traits like race,
gender, and disability. Is body fat an indicator of a character
flaw or of incompetence on the job? Does it pose risks or costs to
employers they should be allowed to evade? Or is it simply a
stigmatized difference that does not bear on the ability to perform
most jobs? Could we imagine fatness as part of workplace diversity?
Considering fat discrimination prompts us to rethink these basic
questions that lawyers, judges, and ordinary citizens ask before a
new trait begins to look suitable for antidiscrimination coverage.
Fat Rights draws on little-known legal cases
brought by fat citizens as well as significant lawsuits over other
forms of bodily difference (such as transgenderism), asking why the
boundaries of our antidiscrimination laws rest where they do.
Fatness, argues Kirkland, is both similar to and provocatively
different from other protected traits, raising long-standing
dilemmas in antidiscrimination law into stark relief. Though
options for defending difference may be scarce, Kirkland evaluates
the available strategies and proposes new ways of navigating this
new legal question. Fat Rights enters the fray of
the obesity debate from a new perspective: our inherited civil
rights tradition. The scope is broad, covering much more than just
weight discrimination and drawing the reader into the larger
context of antidiscrimination protections and how they can be
justified for a new group.
eBook
The double burden of malnutrition: aetiological pathways and consequences for health
Malnutrition has historically been researched and addressed within two distinct silos, focusing either on undernutrition, food insecurity, and micronutrient deficiencies, or on overweight, obesity, and dietary excess. However, through rapid global nutrition transition, an increasing proportion of individuals are exposed to different forms of malnutrition during the life course and have the double burden of malnutrition (DBM) directly. Long-lasting effects of malnutrition in early life can be attributed to interconnected biological pathways, involving imbalance of the gut microbiome, inflammation, metabolic dysregulation, and impaired insulin signalling. Life-course exposure to early undernutrition followed by later overweight increases the risk of non-communicable disease, by imposing a high metabolic load on a depleted capacity for homoeostasis, and in women increases the risk of childbirth complications. These life-course trajectories are shaped both by societal driving factors—ie, rapidly changing diets, norms of eating, and physical activity patterns—and by broader ecological factors such as pathogen burden and extrinsic mortality risk. Mitigation of the DBM will require major societal shifts regarding nutrition and public health, to implement comprehensive change that is sustained over decades, and scaled up into the entire global food system.
Journal Article
Waisted : a novel
In this provocative, wildly entertaining, and compelling novel, seven women enrolled in an extreme weight loss documentary discover self-love and sisterhood as they enact a daring revenge against the exploitative filmmakers.
Book
Global patterns in excess body weight and the associated cancer burden
The prevalence of excess body weight and the associated cancer burden have been rising over the past several decades globally. Between 1975 and 2016, the prevalence of excess body weight in adults-defined as a body mass index (BMI) ≥ 25 kg/m2-increased from nearly 21% in men and 24% in women to approximately 40% in both sexes. Notably, the prevalence of obesity (BMI ≥ 30 kg/m2) quadrupled in men, from 3% to 12%, and more than doubled in women, from 7% to 16%. This change, combined with population growth, resulted in a more than 6‐fold increase in the number of obese adults, from 100 to 671 million. The largest absolute increase in obesity occurred among men and boys in high‐income Western countries and among women and girls in Central Asia, the Middle East, and North Africa. The simultaneous rise in excess body weight in almost all countries is thought to be driven largely by changes in the global food system, which promotes energy‐dense, nutrient‐poor foods, alongside reduced opportunities for physical activity. In 2012, excess body weight accounted for approximately 3.9% of all cancers (544,300 cases) with proportion varying from less than 1% in low‐income countries to 7% or 8% in some high‐income Western countries and in Middle Eastern and Northern African countries. The attributable burden by sex was higher for women (368,500 cases) than for men (175,800 cases). Given the pandemic proportion of excess body weight in high‐income countries and the increasing prevalence in low‐ and middle‐income countries, the global cancer burden attributable to this condition is likely to increase in the future. There is emerging consensus on opportunities for obesity control through the multisectoral coordinated implementation of core policy actions to promote an environment conducive to a healthy diet and active living. The rapid increase in both the prevalence of excess body weight and the associated cancer burden highlights the need for a rejuvenated focus on identifying, implementing, and evaluating interventions to prevent and control excess body weight.
Journal Article