William Smith

Regulation of adipose branched-chain amino acid catabolism enzyme expression and cross-adipose amino acid flux in human obesity

Elevated blood branched-chain amino acids (BCAA) are often associated with insulin resistance and type 2 diabetes, which might result from a reduced cellular utilization and/or incomplete BCAA oxidation. White adipose tissue (WAT) has become appreciated as a potential player in whole body BCAA metabolism. We tested if expression of the mitochondrial BCAA oxidation checkpoint, branched-chain α-ketoacid dehydrogenase (BCKD) complex, is reduced in obese WAT and regulated by metabolic signals. WAT BCKD protein (E1α subunit) was significantly reduced by 35-50% in various obesity models (fa/fa rats, db/db mice, diet-induced obese mice), and BCKD component transcripts significantly lower in subcutaneous (SC) adipocytes from obese vs. lean Pima Indians. Treatment of 3T3-L1 adipocytes or mice with peroxisome proliferator-activated receptor-γ agonists increased WAT BCAA catabolism enzyme mRNAs, whereas the nonmetabolizable glucose analog 2-deoxy-d-glucose had the opposite effect. The results support the hypothesis that suboptimal insulin action and/or perturbed metabolic signals in WAT, as would be seen with insulin resistance/type 2 diabetes, could impair WAT BCAA utilization. However, cross-tissue flux studies comparing lean vs. insulin-sensitive or insulin-resistant obese subjects revealed an unexpected negligible uptake of BCAA from human abdominal SC WAT. This suggests that SC WAT may not be an important contributor to blood BCAA phenotypes associated with insulin resistance in the overnight-fasted state. mRNA abundances for BCAA catabolic enzymes were markedly reduced in omental (but not SC) WAT of obese persons with metabolic syndrome compared with weight-matched healthy obese subjects, raising the possibility that visceral WAT contributes to the BCAA metabolic phenotype of metabolically compromised individuals.

Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity.

The extracellular matrix (ECM) plays an important role in the maintenance of white adipose tissue (WAT) architecture and function, and proper ECM remodeling is critical to support WAT malleability to accommodate changes in energy storage needs. Obesity and adipocyte hypertrophy place a strain on the ECM remodeling machinery, which may promote disordered ECM and altered tissue integrity and could promote proinflammatory and cell stress signals. To explore these questions, new methods were developed to quantify omental and subcutaneous WAT tensile strength and WAT collagen content by three-dimensional confocal imaging, using collagen VI knockout mice as a methods validation tool. These methods, combined with comprehensive measurement of WAT ECM proteolytic enzymes, transcript, and blood analyte analyses, were used to identify unique pathophenotypes of metabolic syndrome and type 2 diabetes mellitus in obese women, using multivariate statistical modeling and univariate comparisons with weight-matched healthy obese individuals. In addition to the expected differences in inflammation and glycemic control, approximately 20 ECM-related factors, including omental tensile strength, collagen, and enzyme transcripts, helped discriminate metabolically compromised obesity. This is consistent with the hypothesis that WAT ECM physiology is intimately linked to metabolic health in obese humans, and the studies provide new tools to explore this relationship.

Single-site robotic cholecystectomy in a broadly inclusive patient population: A prospective study

Objectives:To describe our initial experience with single-site robotic cholecystectomy (SSRC) and its applicability to a broad segment of patients. Background:At the initiation of our study, there were only 3 published reports on SSRC. These initial studies had limited inclusion criteria. We present our experience with the technical aspects and patient outcomes of SSRC in a broadly inclusive patient population. Methods:Prospective cohort study from January 2012 to January 2013, in which 95 patients underwent SSRC. Procedural times, postoperative complications, delayed hospital discharges, and re-admissions were evaluated. Results:Patients were predominantly female (71.6%) had mean age of 45.2 ± 6.1 years and mean body mass index (BMI) of 30.1 ± 7.1 kg/m2. Overall, mean total operative time (TOT) for all patients (n = 95) was 88.63 ± 32.0 (range: 49–220) minutes. SSRC was not completed in 8 (8.42%) patients: 6 conversions to laparoscopy, 1 conversion to open, and 1 aborted case. The group of patients who were able to complete SSRC (n = 87) had a mean TOT of 83.5 ± 24.5 minutes and mean operative robotic time (RT) of 39.6 ± 15.2 minutes. RT was longer in patients with intra-abdominal adhesions (P = 0.0139) and higher BMI (P = 0.03). A minority of patients required hospital admission (11.6%), readmission (6.3%), or reoperation (1.1%). No bile duct injury or death occurred. Conclusions:SSRC is safe and has a manageable learning curve. Patient factors, such as obesity, did not significantly affect conversion rates or TOTs. SSRC is a promising new technique, which can be offered to a wide array of patients.

Increased Soluble Leptin Receptor Levels in Morbidly Obese Patients With Insulin Resistance and Nonalcoholic Fatty Liver Disease

The adipocyte hormone, leptin has been demonstrated to have profibrogenic actions in vitro and in animal models. However, no correlation was found between plasma leptin levels and fibrosis stage in humans. Thus, our aim was to study whether soluble leptin receptor (SLR) or free leptin index (FLI; calculated as the ratio of leptin to SLR), may correlate better with the features of metabolic syndrome and with the histological grade and stage of nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH). We studied a population (n = 104) of morbidly obese patients undergoing bariatric surgery. Data including BMI, type 2 diabetes mellitus, hypertension, and hyperlipidemia were obtained. Plasma fasting leptin and SLR, fasting glucose and insulin were measured, and homeostasis model of assessment insulin resistance (HOMAIR) index and FLI were calculated. All patients had intraoperative liver biopsies. Leptin levels correlated with the BMI. The multiple regression analysis indicated that increasing HOMA and decreasing FLI were predictors of steatosis in the liver (P < 0.0003). SLR levels were positively correlated with the presence of diabetes mellitus and the stage of fibrosis. In conclusion, increased SLR levels in morbidly obese patients with diabetes are correlated with the stage of liver fibrosis, and may reflect progressive liver disease.

Respiratory health effects related to occupational spray painting and welding

Objective: We sought to study respiratory symptoms among automobile assembly workers. Methods: In a cross-sectional study, we compared rates of respiratory symptoms and of physician-diagnosed asthma and COPD in painters and welders to those in assembly workers. Results: Respiratory symptom reporting was significantly increased among welders (odds ratio [OR] = 1.79–2.61) compared with painters or assembly workers, after age, race, and smoking adjustment in multiple logistic regression analyses. Welders also reported significantly more improvement in symptoms on weekends or vacation. However, no significant elevations in adjusted ORs were observed for physician-diagnosed asthma or chronic obstructive pulmonary disease for welders. In contrast, significantly more painters had physician-diagnosed chronic obstructive pulmonary disease (OR = 3.73, 95% confidence interval = 1.27, 11.0). Conclusions: Welders and painters in this plant appeared to have increased risk of respiratory health effects compared with assembly workers.

Greater than expected prevalence of pseudotumor cerebri: a prospective study

BACKGROUND The overall incidence of pseudotumor cerebri (PTC) has been estimated at 1 per 100,000 in the general population, with an increase to 19 per 100,000 among overweight patients. About 25% of affected patients are asymptomatic until they present with vision loss. We hypothesized that PTC would be highly prevalent among obese patients seeking bariatric surgery. The setting of our study was a university hospital. METHODS During a 2-year period, clinical data were collected from candidates for bariatric surgery. A group of the study population was concurrently screened for papilledema using fundus imaging. All images were reviewed by a single neuro-ophthalmologist. All patients with abnormal images were referred for neuro-ophthalmic evaluation. RESULTS The imaging group (78% women) had a mean age of 45.4 ± 10.7 years, and the mean body mass index of 47.8 ± 8.7 kg/m(2). High definition nonmydriatic fundus imaging was normal in 489 patients (91.9%) and abnormal in 43 patients (8.9%). The subsequent evaluation by the neuro-ophthalmologist revealed ocular abnormalities other than optic disc edema in 27 patients (5.1%) and normal findings in 7 patients (1.3%). Five patients (.9%) declined additional evaluation. Four patients (.8%) had confirmed optic disc edema and normal brain magnetic resonance imaging findings. Of these patients, 3 underwent lumbar puncture, which confirmed the diagnosis of PTC. CONCLUSION We identified a greater prevalence of PTC overall (.65%) and in the imaging group (.9%) than previously reported or would have been predicted from the current data. Although routine funduscopic examination is of limited utility, these findings warrant additional investigation into the utility of, and optimal method for, screening morbidly obese patients for this co-morbidity.

Undiagnosed papilledema in a morbidly obese patient population: A prospective study

Background Idiopathic intracranial hypertension (IIH) is a rare condition that can lead to significant morbidity from visual loss. The cause of IIH is unknown, but IIH is known to be associated with obesity. Obese patients may be at particularly high risk for suffering vision loss from IIH. The purpose of the present study is to determine the prevalence of undiagnosed or asymptomatic papilledema in a population of morbidly obese individuals and to determine if these patients should undergo routine screening for papilledema. Methods Patients presenting to the UC Davis Bariatric Surgery Clinic between February 2008 and January 2011 who met the National Institutes of Health criteria for bariatric surgery were invited to participate in the study. Those patients who met the inclusion criteria and consented to the study were included. Participants were screened for IIH by nonmydriatic fundus photographs and by concerning symptoms prompting direct referral for neuro-ophthalmologic evaluation. Images were reviewed by a neuro-ophthalmologist, and patients with suspicious optic discs underwent neuro-ophthalmologic evaluation. Patients with findings consistent with IIH were sent for neurological evaluation. Results A total of 606 patients with an average body mass index of 47 kg/m2 were included in the study. Seventeen of these patients had photographic optic disc findings or symptoms suspicious for IIH. Seven of these patients did not have disc edema on clinical examination. Six patients were not evaluated in the clinic. Four of the 17 patients had subtle optic disc edema confirmed by clinical evaluation and were referred for full neurological workup. These 4 patients had normal neuroimaging, 3 of whom underwent lumbar punctures with borderline high opening pressures. All 4 patients had unremarkable visual field examinations. Fundus abnormalities other than optic disc edema were discovered in 33 patients. Conclusion Our study suggests that in a morbidly obese patient population, papilledema with significant visual loss is rare. Routine screening with fundus photography of morbidly obese patients likely is not warranted.