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The transmembrane 6 superfamily member 2 (TM6SF2) loss-of-function variant rs58542926 is a genetic risk factor for nonalcoholic fatty liver disease and progression to fibrosis but is paradoxically associated with lower levels of hepatically derived triglyceride-rich lipoproteins. TM6SF2 is expressed predominantly in liver and small intestine, sites for triglyceride-rich lipoprotein biogenesis and export. In light of this, we hypothesized that TM6SF2 may exhibit analogous effects on both liver and intestine lipid homeostasis. To test this, we genotyped rs58542926 in 983 bariatric surgery patients from the Geisinger Medical Center for Nutrition and Weight Management, Geisinger Health System, in Pennsylvania and from 3,556 study participants enrolled in the Amish Complex Disease Research Program. Although these two cohorts have different metabolic profiles, carriers in both cohorts had improved fasting lipid profiles. Importantly, following a high-fat challenge, carriers in the Amish Complex Disease Research Program cohort exhibited significantly lower postprandial serum triglycerides, suggestive of a role for TM6SF2 in the small intestine. To gain further insight into this putative role, effects of TM6SF2 deficiency were studied in a zebrafish model and in cultured human Caco-2 enterocytes. In both systems TM6SF2 deficiency resulted in defects in small intestine metabolism in response to dietary lipids, including significantly increased lipid accumulation, decreased lipid clearance, and increased endoplasmic reticulum stress. CONCLUSIONS These data strongly support a role of TM6SF2 in the regulation of postprandial lipemia, potentially through a similar function for TM6SF2 in the lipidation and/or export of both hepatically and intestinally derived triglyceride-rich lipoproteins. (Hepatology 2017;65:1526-1542).

We sought to identify the major risk factors associated with mortality in Roux-en-Y gastric bypass (RYGB) surgery.Bariatric surgery has become an established treatment for extreme obesity. Bariatric surgery mortality has steadily declined with current rates of less than 0.5%. However, significant variation in the mortality rates has been reported for specific patient cohorts and among bariatric centers.Clinical outcome data from 185,315 bariatric surgery patients from the Bariatric Outcome Longitudinal Database were reviewed. Of these, 157,559 patients had either documented 30 or more day follow-up data, including mortality. Multiple demographic, socioeconomic, and clinical factors were analyzed by univariate analysis for their association with 30-day mortality after gastric bypass. Variables found to be significant were entered into a multiple logistic regression model to identify factors independently associated with 30-day mortality. On the basis of these results, a RYGB mortality risk score was developed.The overall 30-day mortality rate for the entire bariatric surgery cohort was 0.1%. Of the 81,751 RYGB patients, the mortality rate was 0.15%. Factors significantly associated with 30-day gastric bypass mortality included increasing body mass index (BMI) (P0.0001), increasing age (P0.005), male gender (P0.001), pulmonary hypertension (P0.0001), congestive heart failure (P=0.0008), and liver disease (P=0.038). When the RYGB risk score was applied, a significant trend (P0.0001) between increasing risk score and mortality rate is found.Increasing BMI, increasing age, male gender, pulmonary hypertension, congestive heart failure, and liver disease are risk factors for 30-day mortality after RYGB. The RYGB risk score can be used to determine patients at greater risk for mortality after RYGB surgery.

Purpose of review Despite being one of the most prevalent chronic diseases, obesity was not recognized as such until very recently. Although linked to ubiquitous diseases like diabetes, hypertension, coronary artery disease, obstructive sleep apnea, and many others, targeted treatments are few. Diet, exercise, and behavior modification are the pillars of weight loss. When they alone do not achieve the required weight reduction, medications may be used for patients with a BMI above 30 or above 27 if obesity-related comorbidities are present. The spectrum of pharmacologic agents aimed at obesity treatment will be reviewed. Recent findings Two medications, phentermine and orlistat, have been the only agents approved many years ago and now still standing. Others have come and gone, removed from the market by the Food and Drug Administration (FDA) because of harmful side-effects. However, in the last few years, new drugs have started to emerge. Since 2012, two new medications phentermine-topiramate extended-release combination and lorcaserin have been FDA approved, while at least one more, naltrexone SR/bupropion SR combination is expected to be re-evaluated by the FDA in 2014. Summary Treating obesity is crucial as it will ultimately result in the prevention of many related chronic diseases and will decrease morbidity and mortality. Weight loss medications are a valuable part of the clinician's toolbox in the treatment of obesity and should be used when appropriate. Having a variety of medications would be a great asset to accommodate various patients' needs and pre-existing medical conditions.

Purpose: Roux-en-Y gastric bypass surgery has become an increasingly common form of weight management. Early retrospective reviews have suggested that new onset nephrolithiasis develops in some patients after undergoing Roux-en-Y gastric bypass. We present a prospective longitudinal study to assess risk factors for nephrolithiasis after Roux-en-Y gastric bypass.Materials and Methods: A total of 45 morbidly obese patients scheduled to undergo Roux-en-Y gastric bypass surgery were enrolled in this prospective study between November 2006 and November 2007. Exclusion criteria included history of nephrolithiasis or inflammatory bowel disease. Serum uric acid, parathyroid hormone, calcium, albumin, and creatinine and 24-hour urine collections were obtained within 6 months before Roux-en-Y gastric bypass, and at 6 to 12 months postoperatively. A Wilcoxon signed-rank test was used to compare preoperative and postoperative serum laboratory values and 24-hour urine values. McNemar's test was used to determine if th...