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Kaplan, Lee

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Lee

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Kaplan, Lee
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    Advantages of Percent Weight Loss as a Method of Reporting Weight Loss after Roux-en-Y Gastric Bypass
    (2012) Hatoum, Ida; Kaplan, Lee
    Objective: Although Roux-en-Y gastric bypass (RYGB) is a generally effective treatment for severe obesity, weight loss (WL) after this operation is highly variable. Accurate predictors of outcome would thus be useful in identifying those patients who would most benefit from this invasive therapy. WL has been characterized using several different metrics, including the number of BMI units lost (ΔBMI), percent baseline WL (%WL), and percent excess body WL (%EBWL). To identify clinically relevant predictors most sensitively it is necessary to avoid confounding by other factors, including preoperative BMI (pBMI), the strongest known predictor of RYGB-induced WL. Design and Methods To determine the WL measure least associated with pBMI, we analyzed outcomes of 846 patients undergoing RYGB. Results: Patients in this cohort had an average pBMI of 50.0 kg/m2. At weight nadir, they lost an average 19.4 kg/m2, 38.7% WL, and 81.2% EBWL. pBMI was strongly and positively associated with ΔBMI at both one year (r=0.56, p=4.7×10−51) and nadir (r=0.58, p=2.8×10−77) and strongly but negatively associated with %EBWL at one year (r=−0.52, p=3.8×10−44) and nadir (r=−0.45, p=7.2×10−43). In contrast, pBMI was not significantly associated with %WL at one year (r=0.04, p=0.33), and only weakly associated at nadir (r=0.13, p=0.0002). Conclusions: Of the metrics examined, %WL is the parameter describing WL after RYGB least influenced by pBMI. It thus improves comparison of WL outcomes across studies of patients undergoing surgery and facilitates the most sensitive identification of novel predictors of surgery-induced WL. We therefore recommend that %WL be adopted more broadly in reporting weight loss after RYGB.
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    Inverse Regulation of Inflammation and Mitochondrial Function in Adipose Tissue Defines Extreme Insulin Sensitivity in Morbidly Obese Patients
    (American Diabetes Association, 2013) Qatanani, Mohammed; Tan, Yejun; Dobrin, Radu; Greenawalt, Danielle M.; Hu, Guanghui; Zhao, Wenqing; Olefsky, Jerrold M.; Sears, Dorothy D.; Kaplan, Lee; Kemp, Daniel M.
    Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes and cardiovascular disease. However, not all obese individuals are insulin resistant, which confounds our understanding of the mechanistic link between these conditions. We conducted transcriptome analyses on 835 obese subjects with mean BMI of 48.8, on which we have previously reported genetic associations of gene expression. Here, we selected ∼320 nondiabetic (HbA1c <7.0) subjects and further stratified the cohort into insulin-resistant versus insulin-sensitive subgroups based on homeostasis model assessment–insulin resistance. An unsupervised informatics analysis revealed that immune response and inflammation-related genes were significantly downregulated in the omental adipose tissue of obese individuals with extreme insulin sensitivity and, to a much lesser extent, in subcutaneous adipose tissue. In contrast, genes related to β-oxidation and the citric acid cycle were relatively overexpressed in adipose of insulin-sensitive patients. These observations were verified by querying an independent cohort of our published dataset of 37 subjects whose subcutaneous adipose tissue was sampled before and after treatment with thiazolidinediones. Whereas the immune response and inflammation pathway genes were downregulated by thiazolidinedione treatment, β-oxidation and citric acid cycle genes were upregulated. This work highlights the critical role that omental adipose inflammatory pathways might play in the pathophysiology of insulin resistance, independent of body weight.
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    Weight Loss, Saline Loading, and the Natriuretic Peptide System
    (Ovid Technologies (Wolters Kluwer Health), 2015) Arora, P.; Reingold, J.; Baggish, Aaron; Guanaga, Derek Philip; Wu, Connie; Ghorbani, Anahita; Song, Y.; Chen-Tournaux, A.; Khan, A. M.; Tainsh, L. T.; Buys, Emmanuel; Williams, Jonathan; Heublein, D. M.; Burnett, J. C.; Semigran, Marc J.; Bloch, K. D.; Scherrer-Crosbie, Marielle; Newton-Cheh, Christopher; Kaplan, Lee; Wang, T. J.
    Background-—In epidemiologic studies, obesity has been associated with reduced natriuretic peptide (NP) concentrations. Reduced NP production could impair the ability of obese individuals to respond to salt loads, increasing the risk of hypertension and other disorders. We hypothesized that weight loss enhances NP production before and after salt loading. Methods and Results-—We enrolled 15 obese individuals (mean BMI 45 5.4 kg/m2) undergoing gastric bypass surgery. Before and 6 months after surgery, subjects were admitted to the clinical research center and administered a large-volume intravenous saline challenge. Echocardiography and serial blood sampling were performed. From the pre-operative visit to 6 months after surgery, subjects had a mean BMI decrease of 27%. At the 6-month visit, N-terminal pro-atrial NP (Nt-proANP) levels were 40% higher before, during, and after the saline infusion, compared with levels measured at the same time points during the pre-operative visit (P<0.001). The rise in Nt-pro-ANP induced by the saline infusion (50%) was similar both before and after surgery (saline, P<0.001; interaction, P=0.2). Similar results were obtained for BNP and Nt-proBNP; resting concentrations increased by 50% and 31%, respectively, after gastric bypass surgery. The increase in NP concentrations after surgery was accompanied by significant decreases in mean arterial pressure (P=0.004) and heart rate (P<0.001), and an increase in mitral annular diastolic velocity (P=0.02). Conclusion-—In obese individuals, weight loss is associated with a substantial increase in the “setpoint” of circulating NP concentrations. Higher NP concentrations could contribute to an enhanced ability to handle salt loads after weight loss.
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    Genome-wide identification of microRNAs regulating cholesterol and triglyceride homeostasis
    (Springer Nature, 2015) Wagschal, Alexandre; Najafi-Shoushtari, S Hani; Wang, Lifeng; Goedeke, Leigh; Sinha, Sumita; deLemos, Andrew S; Black, Josh C; Ramírez, Cristina M; Li, Yingxia; Tewhey, Ryan; Hatoum, Ida; Shah, Naisha; Lu, Yong; Kristo, Fjoralba; Psychogios, Nikolaos; Vrbanac, Vladimir; Lu, Yi-Chien; Hla, Timothy; de Cabo, Rafael; Tsang, John S; Schadt, Eric; Sabeti, Pardis; Kathiresan, Sekar; Cohen, David E.; Whetstine, Johnathan; Chung, Raymond; Fernández-Hernando, Carlos; Kaplan, Lee; Bernards, Andre; Gerszten, Robert; Naar, Anders
    Genome-wide association studies (GWASs) have linked genes to various pathological traits. However, the potential contribution of regulatory noncoding RNAs, such as microRNAs (miRNAs), to a genetic predisposition to pathological conditions has remained unclear. We leveraged GWAS meta-analysis data from >188,000 individuals to identify 69 miRNAs in physical proximity to single-nucleotide polymorphisms (SNPs) associated with abnormal levels of circulating lipids. Several of these miRNAs (miR-128-1, miR-148a, miR-130b, and miR-301b) control the expression of key proteins involved in cholesterol-lipoprotein trafficking, such as the low-density lipoprotein (LDL) receptor (LDLR) and the ATP-binding cassette A1 (ABCA1) cholesterol transporter. Consistent with human liver expression data and genetic links to abnormal blood lipid levels, overexpression and antisense targeting of miR-128-1 or miR-148a in high-fat diet–fed C57BL/6J and Apoe-null mice resulted in altered hepatic expression of proteins involved in lipid trafficking and metabolism, and in modulated levels of circulating lipoprotein-cholesterol and triglycerides. Taken together, these findings support the notion that altered expression of miRNAs may contribute to abnormal blood lipid levels, predisposing individuals to human cardiometabolic disorders.
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    The Role of Obesity Training in Medical School and Residency on Bariatric Surgery Knowledge in Primary Care Physicians
    (Hindawi Publishing Corporation, 2015) Stanford, Fatima; Johnson, Erica D.; Claridy, Mechelle D.; Earle, Rebecca L.; Kaplan, Lee
    Objective:. US primary care physicians are inadequately educated on how to provide obesity treatment. We sought to assess physician training in obesity and to characterize the perceptions, beliefs, knowledge, and treatment patterns of primary care physicians. Methods:. We administered a cross-sectional web-based survey from July to October 2014 to adult primary care physicians in practices affiliated with the Massachusetts General Hospital (MGH). We evaluated survey respondent demographics, personal health habits, obesity training, knowledge of bariatric surgery care, perceptions, attitudes, and beliefs regarding the etiology of obesity and treatment strategies. Results:. Younger primary care physicians (age 20–39) were more likely to have received some obesity training than those aged 40–49 (OR: 0.08, 95% CI: 0.008–0.822) or those 50+ (OR: 0.03, 95% CI: 0.004–0.321). Physicians who were young, had obesity, or received obesity education in medical school or postgraduate training were more likely to answer bariatric surgery knowledge questions correctly. Conclusions:. There is a need for educational programs to improve physician knowledge and competency in treating patients with obesity. Obesity is a complex chronic disease, and it is important for clinicians to be equipped with the knowledge of the multiple treatment modalities that may be considered to help their patients achieve a healthy weight.
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    Liver and Adipose Expression Associated SNPs are Enriched for Association to Type 2 Diabetes
    (Public Library of Science, 2010) Zhong, Hua; Beaulaurier, John; Lum, Pek Yee; Molony, Cliona; MacNeil, Douglas J.; Weingarth, Drew T.; Greenawalt, Danielle; Dobrin, Radu; Hao, Ke; Woo, Sangsoon; Fabre-Suver, Christine; Qian, Su; Tota, Michael R.; Keller, Mark P.; Kendziorski, Christina M.; Yandell, Brian S.; Castro, Victor; Attie, Alan D.; Schadt, Eric E.; Yang, Xia; Zhang, Bin; Kaplan, Lee
    Genome-wide association studies (GWAS) have demonstrated the ability to identify the strongest causal common variants in complex human diseases. However, to date, the massive data generated from GWAS have not been maximally explored to identify true associations that fail to meet the stringent level of association required to achieve genome-wide significance. Genetics of gene expression (GGE) studies have shown promise towards identifying DNA variations associated with disease and providing a path to functionally characterize findings from GWAS. Here, we present the first empiric study to systematically characterize the set of single nucleotide polymorphisms associated with expression (eSNPs) in liver, subcutaneous fat, and omental fat tissues, demonstrating these eSNPs are significantly more enriched for SNPs that associate with type 2 diabetes (T2D) in three large-scale GWAS than a matched set of randomly selected SNPs. This enrichment for T2D association increases as we restrict to eSNPs that correspond to genes comprising gene networks constructed from adipose gene expression data isolated from a mouse population segregating a T2D phenotype. Finally, by restricting to eSNPs corresponding to genes comprising an adipose subnetwork strongly predicted as causal for T2D, we dramatically increased the enrichment for SNPs associated with T2D and were able to identify a functionally related set of diabetes susceptibility genes. We identified and validated malic enzyme 1 (Me1) as a key regulator of this T2D subnetwork in mouse and provided support for the association of this gene to T2D in humans. This integration of eSNPs and networks provides a novel approach to identify disease susceptibility networks rather than the single SNPs or genes traditionally identified through GWAS, thereby extracting additional value from the wealth of data currently being generated by GWAS.
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    Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study
    (Public Library of Science, 2009) Hägg, Sara; Skogsberg, Josefin; Lundström, Jesper; Noori, Peri; Nilsson, Roland; Zhong, Hua; Maleki, Shohreh; Shang, Ming-Mei; Brinne, Björn; Bradshaw, Maria; Bajic, Vladimir B.; Samnegård, Ann; Silveira, Angela; Gigante, Bruna; Leander, Karin; de Faire, Ulf; Rosfors, Stefan; Lockowandt, Ulf; Liska, Jan; Konrad, Peter; Takolander, Rabbe; Franco-Cereceda, Anders; Schadt, Eric E.; Ivert, Torbjörn; Hamsten, Anders; Tegnér, Jesper; Björkegren, Johan; Kerr, Kathleen; Kaplan, Lee
    Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10\(^{−27and−30}\)). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research.
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    The Role of Obesity Training in Medical School and Residency on Bariatric Surgery Knowledge in Primary Care Physicians
    (Hindawi Limited, 2015) Stanford, Fatima; Johnson, Erica D.; Claridy, Mechelle D.; Earle, Rebecca L.; Kaplan, Lee
    Objective. US primary care physicians are inadequately educated on how to provide obesity treatment. We sought to assess physician training in obesity and to characterize the perceptions, beliefs, knowledge, and treatment patterns of primary care physicians. Methods. We administered a cross-sectional web-based survey from July to October 2014 to adult primary care physicians in practices a liated with the Massachusetts General Hospital (MGH). We evaluated survey respondent demographics, personal health habits, obesity training, knowledge of bariatric surgery care, perceptions, attitudes, and beliefs regarding the etiology of obesity and treatment strategies. Results. Younger primary care physicians (age 20–39) were more likely to have received some obesity training than those aged 40–49 (OR: 0.08, 95% CI: 0.008–0.822) or those 50+ (OR: 0.03, 95% CI: 0.004–0.321). Physicians who were young, had obesity, or received obesity education in medical school or postgraduate training were more likely to answer bariatric surgery knowledge questions correctly. Conclusions. ere is a need for educational programs to improve physician knowledge and competency in treating patients with obesity. Obesity is a complex chronic disease, and it is important for clinicians to be equipped with the knowledge of the multiple treatment modalities that may be considered to help their patients achieve a healthy weight.