Faculty Bibliography

PURPOSE/OBJECTIVE:Understanding the effects of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on adipose tissue physiology is important for the treatment of obesity-related metabolic disorders. By using robust mouse models of bariatric surgery that closely resemble those performed in humans, we can compare the effects of RYGB and VSG on adipose physiology in the absence of post-operative confounds such as diet and lifestyle changes. MATERIALS AND METHODS/METHODS:RYGB and VSG were compared using a diet-induced mouse model of obesity. High-fat diet (HFD) was administered post-operatively and changes to white and brown adipose tissue were evaluated, along with alterations to weight, glucose homeostasis, dyslipidemia, and insulin sensitivity. RESULTS:After prolonged exposure to high-fat diet post-operatively, RYGB was effective in achieving sustained weight loss, while VSG unexpectedly accelerated weight gain rates. The resolution of obesity-related comorbidities such as glucose and insulin intolerance, dyslipidemia, and insulin sensitivity was improved after RYGB, but not for VSG. In RYGB, there were improvements to the function and health of white adipose tissue, enhanced brown adipose metabolism, and the browning of subcutaneous white adipose tissue, with no comparable changes seen for these factors after VSG. Some markers of systemic inflammation improved after both RYGB and VSG. CONCLUSION/CONCLUSIONS:There are significantly different effects between RYGB and VSG when HFD is administered post-operatively and robust mouse models of bariatric surgery are used. RYGB resulted in lasting physiological and metabolic changes but VSG showed little difference from that of its sham-operated, DIO counterpart.

BACKGROUND:- There is a paucity of data describing the effects of COVID-19, especially in asymptomatic patients, on placental pathology. Although the pathophysiology of COVID-19 is not completely understood, there is emerging evidence that it causes a severe systemic inflammatory response and results in a hypercoagulable state with widespread microthrombi. We hypothesized that it is plausible that a similar disease process may occur in the fetal-maternal unit. OBJECTIVE:- The aim of this study was to determine whether COVID-19 in term patients admitted to Labor and Delivery, including women without COVID-19 symptomatology, is associated with increased placental injury compared to a cohort of COVID-19 negative controls. STUDY DESIGN/METHODS:- This was a retrospective cohort study performed at NYU Winthrop Hospital between 3/31/2020 and 6/17/2020. During the study period all women admitted to Labor and Delivery were routinely tested for SARS-CoV-2 regardless of symptomatology. The placental histopathological findings of COVID-19 patients (n=77) who delivered a singleton gestation at term were compared to a control group of term patients without COVID-19 (n=56). Controls were excluded if they had obstetric or medical complications including fetal growth restriction, oligohydramnios, hypertension, diabetes, coagulopathy or thrombophilia. Multivariable logistic regression models were performed for variables that were significant in univariable analyses. A subgroup analysis was also performed comparing asymptomatic COVID-19 cases to negative controls. RESULTS:- In univariable analyses, COVID-19 cases were more likely to have evidence of fetal vascular malperfusion, i.e. presence of avascular villi and/or mural fibrin deposition (32.5% (25/77) vs. 3.6% (2/56), p<0.0001) and villitis of unknown etiology (20.8% (16/77) vs. 7.1% (4/56), p=0.030). These findings persisted in a subgroup analysis of asymptomatic COVID-19 cases compared to COVID-19 negative controls. In a multivariable model adjusting for maternal age, race/ethnicity, mode of delivery, preeclampsia, fetal growth restriction and oligohydramnios, the frequency of fetal vascular malperfusion abnormalities remained significantly higher in the COVID-19 group (OR= 12.63, 95% CI [2.40, 66.40]). While the frequency of villitis of unknown etiology was more than double in COVID-19 cases compared to controls, this did not reach statistical significance in a similar multivariable model (OR=2.11, 95% CI [0.50, 8.97]). All neonates of mothers with COVID-19 tested negative for SARS-CoV-2 by PCR. CONCLUSIONS:- Despite the fact that all neonates born to mothers with COVID-19 were negative for SARS-CoV-2 by PCR, we found that COVID-19 in term patients admitted to Labor and Delivery is associated with increased rates of placental histopathologic abnormalities, particularly fetal vascular malperfusion and villitis of unknown etiology. These findings appear to occur even among asymptomatic term patients.

There is controversy over whether African Americans have higher vitamin D requirements than recommended by the Institute of Medicine. We previously reported that maintaining serum 25(OH)D above 30 ng/mL does not prevent age-related bone loss. Herein, we report that bone strength is also unaffected by maintaining this level in this population.

Non-alcoholic fatty liver disease (NAFLD) is an emerging risk factor for type 2 diabetes mellitus, cardiovascular disease, and all-cause mortality. Previously, we demonstrated that lipocalin-type prostaglandin D₂ synthase (L-PGDS) knockout mice show increased glucose intolerance and accelerated atherosclerosis. In the present study, we investigated the role of L-PGDS in mediating NAFLD utilizing L-PGDS knockout (KO) and control C57BL/6 mice fed either low fat (LFD) or high fat diet (HFD) for 14 weeks. Our present study demonstrates that L-PGDS KO mice remain slightly lighter in weight compared to control mice, yet develop NAFLD faster and eventually progress to the more severe non-alcoholic steatohepatitis (NASH). We found increased lipid accumulation in the liver of KO mice over time on both diets, as compared to control mice. The L-PGDS KO mice showed elevated fasting glucose and insulin levels and developed insulin resistance on both LFD and HFD. Lipogenesis marker proteins such as SREBP-1c and LXRα were increased in L-PGDS KO mice after 14 weeks on both diets, when compared to control mice. We replicated our in vivo findings in vitro using HepG2 cells treated with a combination of free fatty acids (oleic and palmitic acid) and exposure to a L-PGDS inhibitor and prostaglandin D₂ receptor (DP1) antagonists. We conclude that the absence or inhibition of L-PGDS results in dyslipidemia, altered expression of lipogenesis genes and the acceleration of NAFLD to NASH, independent of diet and obesity. We propose L-PGDS KO mice as a useful model to explore the pathogenesis of NAFLD and NASH, and L-PGDS as a potential therapeutic target for treatment.

RATIONALE:Increasing prevalence of obesity and its associated risk with cardiovascular diseases demands a better understanding of the contribution of different cell types within this complex disease for developing new treatment options. Previous studies could prove a fundamental role of FTO (fat mass and obesity-associated protein) within obesity; however, its functional role within different cell types is less understood. OBJECTIVES:We identify endothelial FTO as a previously unknown central regulator of both obesity-induced metabolic and vascular alterations. METHODS AND RESULTS:application. CONCLUSIONS:These data identify endothelial FTO as a previously unknown regulator in the development of obesity-induced metabolic and vascular changes, which is independent of its known function in regulation of obesity.

Reviewed here are multiple mouse models of vertical sleeve gastrectomy (VSG) and Roux-en Y gastric bypass (RYGB) that have emerged over the past decade. These models use diverse approaches to both operative and perioperative procedures. Scrutinizing the benefits and pitfalls of each surgical model and what to expect in terms of post-operative outcomes will enhance our assessment of studies using mouse models, as well as advance our understanding of their translational potential. Two mouse models of bariatric surgery, VSG-lembert and RYGB-small pouch, demonstrate low mortality and most closely recapitulate the human forms of surgery. The use of liquid diets can be minimized, and in mice, RYGB demonstrates more reliable and longer lasting effects on weight loss compared to that of VSG.

The transcription factor aryl hydrocarbon receptor nuclear translocator-like protein-1 (BMAL1) is an essential regulator of the circadian clock, which controls the 24-h cycle of physiological processes such as nutrient absorption. To examine the role of BMAL1 in small intestinal glucose absorption, we used differentiated human colon adenocarcinoma cells (Caco-2 cells). Here, we show that BMAL1 regulates glucose uptake in differentiated Caco-2 cells and that this process is dependent on the glucose transporter sodium-glucose cotransporter 1 (SGLT1). Mechanistic studies show that BMAL1 regulates glucose uptake by controlling the transcription of SGLT1 involving paired-homeodomain transcription factor 4 (PAX4), a transcriptional repressor. This is supported by the observation that clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated endonuclease Cas9 (Cas9) knockdown of PAX4 increases SGLT1 and glucose uptake. Chromatin immunoprecipitation (ChIP) and ChIP-quantitative PCR assays show that the knockdown or overexpression of BMAL1 decreases or increases the binding of PAX4 to the hepatocyte nuclear factor 1-α binding site of the SGLT1 promoter, respectively. These findings identify BMAL1 as a critical mediator of small intestine carbohydrate absorption and SGLT1.

Context/UNASSIGNED:There is limited information on the influence of vitamin D on physical performance in black Americans. Objective/UNASSIGNED:To determine if maintenance of serum 25(OH)D above 75 nmol/L prevents the decline in physical performance. Design/UNASSIGNED:The PODA trial had a prospective, randomized, placebo controlled, double-dummy design with two arms: one with placebo vitamin D3 adjusted to maintain serum 25(OH)D above 75 nmol/L. Patients/UNASSIGNED:The target population was healthy elderly black women with serum 25(OH)D between 20 and 65 nmol/L. The trial was 3 years in duration with measurement of physical performance every 6-months: Grip strength, Short Physical Performance Battery (SPPB), 10 chair rises and 6-minute walk distance. 260 women entered the study and 184 completed 3 years. Mean age was 68.2 years. Baseline 25(OH)D was 53 nmol/L and total SPPB was 11 (10-12). Setting/UNASSIGNED:Research Center in an Academic Health Center. Main Outcomes Measure/UNASSIGNED:Prevention of decline in physical performance measures. Intervention/UNASSIGNED:Participants were randomly assigned to placebo or active vitamin D. Vitamin D3 dose was adjusted to maintain serum 25(OH)D above 75 nmol/l. Results/UNASSIGNED:There was a decline with time in grip strength and the 6-minute walk. The SPBB increased with time. There were no significant differences between the placebo and active vitamin D3 groups with respect to the temporal patterns observed for any of the performance measures. Conclusions/UNASSIGNED:There is no benefit of maintaining serum 25(OH)D above 75 nmol/L in preventing the decline in physical performance in healthy black American women.

BACKGROUND:Limited information is available on the influence of vitamin D on falls in older high-functioning black American women. Endocrine Society guidelines propose serum 25(OH)D levels over 30 ng/mL. OBJECTIVE:To determine if maintenance of serum 25(OH)D above 30 ng/mL protects against falls. DESIGN/METHODS:adjusted to maintain serum 25(OH)D above 30 ng/mL. The primary outcomes were the prevention of bone loss and the decline in physical performance. PATIENTS/METHODS:The target population was healthy black women older than 60 years with serum 25(OH)D between 8 and 26 ng/mL. The trial was 3 years in duration with a falls questionnaire administered every 3 months. A total of 260 women entered the study, and 184 completed the 3 years. Mean age was 68.2 years. SETTING/METHODS:Research center in an academic health center. MAIN OUTCOMES MEASURE/METHODS:Prevention of falls. INTERVENTION/METHODS:dose was adjusted to maintain serum 25(OH)D above 30 ng/mL in the active group using a double-dummy design. RESULTS:Baseline 25(OH)D was 22 ng/mL. Mean serum 25(OH)D reached 47 ng/mL in the active group compared with 21 ng/mL in the placebo group. There were 14.2% falls in the previous year recalled at baseline. During the study, 46% reported falling in the treatment group compared with 47% in the placebo group. There was no association of serum 25(OH)D or vitamin D dose with the risk of falling. CONCLUSIONS:There is no benefit of maintaining serum 25(OH)D above 30 ng/mL compared with the Institute of Medicine recommendation (20 ng/mL) in preventing falls in healthy older black American women.

OBJECTIVES/OBJECTIVE:To examine the effect of 25-hydroxyvitamin D (25(OH)D) levels recommended by Endocrine Society guidelines (>30 ng/mL) on cognition in healthy older African-American women over 3 years. DESIGN/METHODS:Randomized, double-blind, placebo-controlled clinical trial. SETTING/METHODS:Bone Mineral Research Center at New York University Winthrop Hospital. PARTICIPANTS/METHODS:Healthy postmenopausal African American women aged 65 and older (N=260; mean age 68.2 ± 4.9; 46% college education or higher). INTERVENTION/METHODS:Half of the women were randomized to receive vitamin D (adjusted to achieve a serum level > 30 ng/mL) with calcium (diet and supplement total of 1,200 mg), and half were randomized to receive placebo with calcium (1,200 mg). MEASUREMENTS/METHODS:Cognitive assessments every 6 months using the Mini-Mental State Examination (MMSE) to detect cognitive decline. Mean MMSE scores were calculated over time for both groups. Those with MMSE scores less than 21 at baseline were excluded. RESULTS:was 3,490 ± 1,465 IU per day, and average serum 25(OH)D at 3 years was 46.8 ± 1.2 ng/mL in the active group and 20.7 ± 1.1 ng/mL in the placebo group. Serum 25(OH)D concentration was maintained at greater than 30 ng/mL in 90% of the active group. Over the 3-year period, MMSE scores increased in both groups (p < .001), although change over time was not significantly different between the groups. No adverse events associated with vitamin D were observed. CONCLUSION/CONCLUSIONS:There was no difference in cognition over time between older African-American women with serum concentrations of 25(OH)D of 30 ng/mL and greater than those taking placebo. There is no evidence to support vitamin D intake greater than the recommended daily allowance in this population for preventing cognitive decline.