Faculty Bibliography

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.

Black Americans have lower levels of serum 25(OH)D but superior bone health compared to white Americans. There is controversy over whether they should be screened for vitamin D deficiency and have higher vitamin D requirements than recommended by the Institute of Medicine (IOM). The purpose of this trial was to determine whether Vitamin D supplementation in elderly black women prevents bone loss. A total of 260 healthy black American women, 60 years of age and older were recruited to take part in a two-arm, double-dummy 3-year randomized controlled trial (RCT) of vitamin D₃ versus placebo. The study was conducted in an ambulatory clinical research center. Vitamin D₃ dose was adjusted to maintain serum 25(OH)D above 75 nmol/L. Bone mineral density (BMD) and serum were measured for parathyroid hormone (PTH), C-terminal crosslink telopeptide (CTX), and bone-specific alkaline phosphatase (BSAP) every 6 months. Baseline serum 25(OH)D₃ was 54.8 ± 16.8 nmol/L. There was no group × time interaction effect for any BMD measurement. For all BMD measurements, except for total body and spine, there was a statistically significant negative effect of time (p < 0.001). An equivalency analysis showed that the treatment group was equivalent to the control group. Serum PTH and BSAP declined, with a greater decline of PTH in the treatment group. The rate of bone loss with serum 25(OH)D above 75 nmol/L is comparable to the rate of loss with serum 25(OH)D at the Recommended Dietary Allowance (RDA) of 50 nmol/L. Black Americans should have the same exposure to vitamin D as white Americans. © 2018 American Society for Bone and Mineral Research.

BACKGROUND/OBJECTIVE:Lipocalin Prostaglandin D2 synthase (LPGDS) contributes to the production of PGD2, which has been associated with adipogenesis. In this study, we aimed to investigate the role of PGD2 on obesity through its DP1 and DP2 receptor signaling using intraperitoneal injection of their respective agonists and antagonists. METHODS:mice were divided into five groups: vehicle control (n=5), DP1 receptor agonist (n=5), DP1 receptor antagonist (n=5), DP2 receptor agonist (n=5), and DP2 receptor antagonist (n=5), and the study was carried out for 10 weeks. RESULTS:Despite being on high fat diet, mice receiving DP1 receptor agonist sustained a significant inhibition of weight gain throughout the study gaining only 11.4% body weight compared to the controls gaining 61% body weight. Interestingly, parallel to the body weight, the DP1 receptor agonist group showed a significant reduction in food intake throughout the study. Consistently, fasting leptin, insulin and bile acids levels were elevated in the DP1 receptor agonist group compared to controls. As expected, there was a significant reduction in fasting glucose level in DP1 receptor agonist group. At last, as a result of weight gain inhibition, DP1 receptor agonist also imparted cardiovascular benefits showing significant reduction in aortic wall thickness, intima, adventia and lumen size. CONCLUSION:Based on the obtained results, we believe DP1 receptor agonism inhibited diet induced weight gain possibly through controlling appetite which consequently imparted beneficial cardiometabolic effects. DP1 receptor agonism may represent a novel therapeutic target for the management of obesity.

RATIONALE/BACKGROUND:Vitamin D deficiency is associated with bone loss, poor muscle strength, falls and fracture. This information in older African Americans (AAs) is sparse. OBJECTIVE:The study of the relationship of Physical performance, Osteoporosis prevention with vitamin D in older African Americans (PODA) is a randomized, double-blind, placebo-controlled 3-year trial examining the effect of vitamin D on bone loss and physical performance in older AA women. METHODS:dose was determined by the baseline serum 25OHD level, and adjusted further to maintain serum 25OHD between 30 and 69ng/ml. Subjects with baseline 25OHD levels ≤8ng/ml or ≥26ng/ml were excluded. Objective measures of neuromuscular strength [Short Physical Performance Battery (SPPB), grip strength and 6-minute walking distance (6MWD)] and bone mineral density (BMD) were obtained. RESULTS:SPPB gait speed, grip strength and 6MWD showed a significant positive correlation with free 25OHD. 1pg/ml increase in free 25OHD predicted a 32% increase in the odds of having higher gait speed and a 1.42lb. increase in grip strength. No significant differences in BMI, BMD, muscle mass, grip strength, serum total 25OHD and free 25OHD were observed between groups. None of the measures of physical performance showed an association with baseline serum 25OHD. CONCLUSIONS:This is the first study to show an association between free 25OHD and physical performance. These findings indicate a positive relationship of free 25OHD with gait speed and grip strength in older AA women. Further studies are needed to understand the role of free 25OHD.