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.