Obesity is responsible for more than 300,000 deaths and $117 billion in medical costs annually, but much of our understanding of its pathophysiology derives from studies in rodents. Bariatric surgery offers the best current treatment results in terms of weight-loss and improvement in co-morbidities such as diabetes in patients with moderate obesity, but has been a high risk procedure, with appreciable morbidity and mortality in higher obesity grades. Among obesity co-morbidities, diabetes, hypertension, dyslipidemia, arterio- sclerotic cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD) have common pathogenetic mechanisms involving insulin resistance. This, in turn, relates in incompletely understood ways to the large, metabolically active, intra-abdominal fat depots typical of the """"""""metabolic syndrome"""""""" in the obese, the movement of long chain fatty acids (LCFA) between these depots and the liver, and the """"""""lipotoxicity"""""""" of LCFA for key non-adipose tissues, e.g. the pancreatic beta-cell. We have developed a novel two-stage laparoscopic surgical approach to high-grade obesity. A restrictive sleeve gastrectomy is followed after a -100 Ib weight loss, when the patient is a better surgical risk, by a second procedure that causes malabsorption. Our initial series of high risk patients (BMI >50) has grown to 100 cases with excellent long term weight loss, minimal morbidity, and no mortality, so that this approach has become our treatment of choice for all patients with BMI >60 and those with BMI >50 plus other risk factors. The availably in such patients of paired biopsies of liver and of omental &subcutaneous fat at each operation will allow us to study, for the first time in man, the effects of obesity and weight loss on: [A] Key aspects of adipose tissue biology, including depot-specific effects on adipocyte LCFA uptake and lipolysis, endocrine functions of the adipocyte, and the impact of macrophage infiltration and adipokine production on these functions;[B] Patho- genetic mechanisms of NAFLD, including studies of hepatocellular LCFA and triglyceride (TG) uptake, LCFA synthesis and oxidation, lipoprotein synthesis and TG excretion;and [C] Pathogenesis of the atherogenic dyslipidemia (elevated TG, reduced HDL) of obesity. The studies will document important differences in the pathophysiology of obesity between humans and rodents, and should yield novel insights, with potential therapeutic implications, into mechanisms responsible for its key comorbidities.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK072526-05
Application #
7921995
Study Section
Special Emphasis Panel (ZDK1-GRB-8 (J2))
Program Officer
Horlick, Mary
Project Start
2006-09-15
Project End
2011-08-31
Budget Start
2010-09-01
Budget End
2011-08-31
Support Year
5
Fiscal Year
2010
Total Cost
$329,153
Indirect Cost
Name
Columbia University (N.Y.)
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
Berk, Paul D; Verna, Elizabeth C (2016) Nonalcoholic Fatty Liver Disease: Lipids and Insulin Resistance. Clin Liver Dis 20:245-62
Ge, Fengxia; Walewski, José L; Torghabeh, Mehyar Hefazi et al. (2016) Facilitated long chain fatty acid uptake by adipocytes remains upregulated relative to BMI for more than a year after major bariatric surgical weight loss. Obesity (Silver Spring) 24:113-22
Walewski, José L; Ge, Fengxia; Lobdell 4th, Harrison et al. (2014) Spexin is a novel human peptide that reduces adipocyte uptake of long chain fatty acids and causes weight loss in rodents with diet-induced obesity. Obesity (Silver Spring) 22:1643-52
Hu, Chunguang; Ge, Fengxia; Hyodo, Eiichi et al. (2013) Chronic ethanol consumption increases cardiomyocyte fatty acid uptake and decreases ventricular contractile function in C57BL/6J mice. J Mol Cell Cardiol 59:30-40
King, Wendy C; Engel, Scott G; Elder, Katherine A et al. (2012) Walking capacity of bariatric surgery candidates. Surg Obes Relat Dis 8:48-59
Bradbury, Michael W; Stump, Decherd; Guarnieri, Frank et al. (2011) Molecular modeling and functional confirmation of a predicted fatty acid binding site of mitochondrial aspartate aminotransferase. J Mol Biol 412:412-22
Ge, Fengxia; Lobdell 4th, Harrison; Zhou, Shengli et al. (2010) Digital analysis of hepatic sections in mice accurately quantitates triglycerides and selected properties of lipid droplets. Exp Biol Med (Maywood) 235:1282-6
Ge, Fengxia; Zhou, Shengli; Hu, Chunguang et al. (2010) Insulin- and leptin-regulated fatty acid uptake plays a key causal role in hepatic steatosis in mice with intact leptin signaling but not in ob/ob or db/db mice. Am J Physiol Gastrointest Liver Physiol 299:G855-66
Walewski, Jose L; Ge, Fengxia; Gagner, Michel et al. (2010) Adipocyte accumulation of long-chain fatty acids in obesity is multifactorial, resulting from increased fatty acid uptake and decreased activity of genes involved in fat utilization. Obes Surg 20:93-107
Petrescu, O; Cheema, A F; Fan, X et al. (2008) Differences in adipocyte long chain fatty acid uptake in Osborne-Mendel and S5B/Pl rats in response to high-fat diets. Int J Obes (Lond) 32:853-62

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