Genetics of Obesity: What We Have Learned Over Decades of Research. Bouchard Claude Obesity (Silver Spring, Md.) There is a genetic component to human obesity that accounts for 40% to 50% of the variability in body weight status but that is lower among normal weight individuals (about 30%) and substantially higher in the subpopulation of individuals with obesity and severe obesity (about 60%-80%). The appreciation that heritability varies across classes of BMI represents an important advance. After controlling for BMI, ectopic fat and fat distribution traits are characterized by heritability levels ranging from 30% to 55%. Defects in at least 15 genes are the cause of monogenic obesity cases, resulting mostly from deficiencies in the leptin-melanocortin signaling pathway. Approximately two-thirds of the BMI heritability can be imputed to common DNA variants, whereas low-frequency and rare variants explain the remaining fraction. Diminishing allele effect size is observed as the number of obesity-associated variants expands, with most BMI-increasing or -decreasing alleles contributing only a few grams or less to body weight. Obesity-promoting alleles exert minimal effects in normal weight individuals but have larger effects in individuals with a proneness to obesity, suggesting a higher penetrance; however, it is not known whether these larger effect sizes precede obesity or are caused by an obese state. The obesity genetic risk is conditioned by thousands of DNA variants that make genetically based obesity prevention and treatment a major challenge. 10.1002/oby.23116

Inflammation, obesity, and thrombosis. Samad Fahumiya,Ruf Wolfram Blood Clinical and epidemiological studies support a connection between obesity and thrombosis, involving elevated expression of the prothrombotic molecules plasminogen activator inhibitor-1 and tissue factor (TF) and increased platelet activation. Cardiovascular diseases and metabolic syndrome-associated disorders, including obesity, insulin resistance, type 2 diabetes, and hepatic steatosis, involve inflammation elicited by infiltration and activation of immune cells, particularly macrophages, into adipose tissue. Although TF has been clearly linked to a procoagulant state in obesity, emerging genetic and pharmacologic evidence indicate that TF signaling via G protein-coupled protease-activated receptors (PAR2, PAR1) additionally drives multiple aspects of the metabolic syndrome. TF-PAR2 signaling in adipocytes contributes to diet-induced obesity by decreasing metabolism and energy expenditure, whereas TF-PAR2 signaling in hematopoietic and myeloid cells drives adipose tissue inflammation, hepatic steatosis, and insulin resistance. TF-initiated coagulation leading to thrombin-PAR1 signaling also contributes to diet-induced hepatic steatosis and inflammation in certain models. Thus, in obese patients, clinical markers of a prothrombotic state may indicate a risk for the development of complications of the metabolic syndrome. Furthermore, TF-induced signaling could provide new therapeutic targets for drug development at the intersection between obesity, inflammation, and thrombosis. 10.1182/blood-2013-05-427708

The hematologic consequences of obesity. Purdy Johanna C,Shatzel Joseph J European journal of haematology The prevalence of obesity is increasing and progressively influencing physician-patient interactions. While there is a sizable amount of data demonstrating that obesity is a state of low-grade inflammation, to our knowledge, there is no single review summarizing its effects on hematologic parameters and thrombotic risk. We performed a literature search which largely surfaced observational studies, with a few systematic reviews and meta-analyses of these studies. We took care to review the mechanisms driving an inflammatory state and obesity's effect on white blood cells, red blood cells, platelets, and thrombotic risk. There is an observed relative, and sometimes absolute leukocytosis driven by this inflammatory state. Obesity is also associated with increased platelet counts and an increased risk for venous thromboembolism (VTE). Lastly, the association between obesity, iron deficiency (ID), and red blood cell counts may be present but remains uncertain. Recognizing the above associations may provide clinicians with reassurance regarding otherwise unexplained hematologic abnormalities in obese individuals. We hope this review will prompt future studies to further understand the underlying mechanisms driving these abnormalities and identify modifiable risk factors and potential therapeutic targets to prevent the development of probable obesity-associated conditions with significant morbidity and mortality, such as ID and VTE. 10.1111/ejh.13560