👤 Albert Lecube

Obesity is a polygenic multifactorial disease. Recent genome-wide association studies have identified several common loci associated with obesity-related phenotypes. Bariatric surgery (BS) is the most effective long-term treatment for patients with severe obesity. The huge variability in BS outcomes between patients suggests a moderating effect of several factors, including the genetic architecture of the patients. To examine the role of a genetic risk score (GRS) based on 7 polymorphisms in 5 obesity-candidate genes (FTO, MC4R, SIRT1, LEP, and LEPR) on weight loss after BS. University hospital in Spain. We evaluated a cohort of 104 patients with severe obesity submitted to BS (Roux-en-Y gastric bypass or sleeve gastrectomy) followed up for >60 months (lost to follow-up, 19.23%). A GRS was calculated for each patient, considering the number of carried risk alleles for the analyzed genes. During the postoperative period, the percentage of excess weight loss total weight loss and changes in body mass index were evaluated. Generalized estimating equation models were used for the prospective analysis of the variation of these variables in relation to the GRS. The longitudinal model showed a significant effect of the GRS on the percentage of excess weight loss (P = 1.5 × 10 The use of the GRS in considering the polygenic nature of obesity seems to be a useful tool to better understand the outcome of patients with obesity after BS. Show less

Around 30% of the patients that undergo bariatric surgery (BS) do not reach an appropriate weight loss. The OBEGEN study aimed to assess the added value of genetic testing to clinical variables in predicting weight loss after BS. A multicenter, retrospective, longitudinal, and observational study including 416 patients who underwent BS was conducted (Clinical.Trials.gov- NCT02405949). 50 single nucleotide polymorphisms (SNPs) from 39 genes were examined. Receiver Operating Characteristic (ROC) curve analysis were used to calculate sensitivity and specificity. Satisfactory response to BS was defined as at nadir excess weight loss >50%. A good predictive model of response [area under ROC of 0.845 (95% CI 0.805-0.880), Show less

Diabesity and fatty liver have been associated with low levels of high-density lipoprotein cholesterol, and thus could impair macrophage-specific reverse cholesterol transport (m-RCT). Liver X receptor (LXR) plays a critical role in m-RCT. Abcg5/g8 sterol transporters, which are involved in cholesterol trafficking into bile, as well as other LXR targets, could be compromised in the livers of obese individuals. We aimed to determine m-RCT dynamics in a mouse model of diabesity, the db/db mice. These obese mice displayed a significant retention of macrophage-derived cholesterol in the liver and reduced fecal cholesterol elimination compared with nonobese mice. This was associated with a significant downregulation of the hepatic LXR targets, including Abcg5/g8. Pharmacologic induction of LXR promoted the delivery of total tracer output into feces in db/db mice, partly due to increased liver and small intestine Abcg5/Abcg8 gene expression. Notably, a favorable upregulation of the hepatic levels of ABCG5/G8 and NR1H3 was also observed postoperatively in morbidly obese patients, suggesting a similar LXR impairment in these patients. In conclusion, our data show that downregulation of the LXR axis impairs cholesterol transfer from macrophages to feces in db/db mice, whereas the induction of the LXR axis partly restores impaired m-RCT by elevating the liver and small intestine expressions of Abcg5/g8. Show less