Faculty & Staff at TUC
Department: Basic Sciences
Title: Director MRC and Interim Associate Dean of Research
Phone: (707) 638-5456
Fax: (707) 638-5438
Office: Administration and Faculty 1, Rm. 125
|Institution||Degree||Field of Study||Obtained|
|Lausanne University, Switzerland||BS||Biochemistry/Physiology||1985|
|Lausanne University, Switzerland||PhD||Metabolism/Physiology||1990|
|University of Texas Medical Branch, Galveston, TX||Postdoc||Metabolism/Tracer methods||1992|
|University of California, Berkeley, CA||Postdoc||Metabolism/Nutrition||1994|
PA 600: Basic Science Foundations (Course Director)
PA617: Clinical Medicine III (Participating Faculty Member)
OMS program Elective (Participating Faculty Member)
We felt that simultaneous study of the interplay between hepatic de novo lipogenesis (DNL), glucose production and gluconeogenesis (GNG) would lead to a better understanding of the pathophysiology at the origins of hypertriglyceridemia and hyperglycemia. Indeed, de novo lipogenesis (DNL), the pathway converting CHO to fat shares precursors with the GNG pathway and is a biochemical bridge between CHO and fat metabolism. This latter fact and our preliminary studies led me to hypothesize that hepatic DNL was an important regulatory pathway for diverting part of the GNG flux to better control GNG and glucose production.
We chose three main approaches to test this hypothesis in humans. One approach was to stimulate hepatic DNL by energy overfeeding with CHO or by feeding energy-balanced high CHO diets, and to monitor how this affected glucose production in healthy controls. The second approach was to utilize insulin resistant patients (such as obese and critically ill patients) who often have defects in glucose homeostasis and determine how these defects impacted DNL. The third approach was to test if inhibition of hepatic DNL had an impact on GNG and glucose production. The use of fructose as both a potent gluconeogenic and lipogenic precursor emphasized the importance of DNL in glucose homeostasis.
SCHWARZ, JEAN-MARC & HAVEL, PETER J
FATTY ACID SOURCES OF FRUCTOSE AND HFCS-INDUCED POSTPRANDIAL HYPERTRIGLYCERIDEMIA
The parent study for this proposed ancillary study is an NIH/NHLBI-funded investigation comparing the effects of consuming sweetened beverages for 2 weeks in young (18-40 years), normal weight and overweight/obese adults (5R01HL091333-02: Effects of 2wk fructose & HFCS consumption on lipid dysregulation & insulin resistance). Baseline experimental procedures (including 24-h serial blood sampling) are conducted while subjects reside as inpatients at the CTSC-funded Clinical Research Center (CCRC) for 3.5 days and consume an energy-balanced, high complex carbohydrate diet. Subjects then consume sweetened beverages providing 25% of energy requirements as fructose, glucose, or high fructose corn syrup (HFCS); or 0, 10, or 17.5% of energy as fructose or HFCS along with their usual ad libitum diet. At the end of the 2-week intervention, subjects return to the CCRC and the same experimental procedures are performed while subjects consume an energy-balanced diet, which includes the assigned sweetened beverages. The early results from this investigation indicate that consumption of HFCS-sweetened beverages at 25% of energy results in significant increases of late-night postprandial triglyceride (TG) concentrations, and of fasting LDL cholesterol and apolipoprotein-B (ApoB) concentrations that are comparable in magnitude to those observed after consumption of beverages sweetened with 100% fructose. Consumption of glucose-sweetened beverages does not alter these parameters. There is considerable evidence to support the hypothesis that postprandial hypertriglyceridemia is a key metabolic disturbance that gives rise to the lipid dysregulation characteristic of metabolic syndrome and type 2 diabetes. The purpose of this proposal is to investigate the mechanisms that contribute to the postprandial hypertriglyceridemia induced by fructose and HFCS consumption by quantifying the absolute and proportional contributions of fatty acids derived from de novo lipogenesis (DNL), diet, and free fatty acids (FFA) from adipose TG lipolysis to fasting and postprandial levels of triglyceride-rich lipoproteins (TRL). Stable isotopes will be administered (via oral consumption and 26-h intravenous infusions) to subsets of subjects during the 24-h serial blood sampling protocols that are conducted in all study participants during consumption of energy-balanced, high complex carbohydrate meals at baseline, and meals consumed with beverages sweetened with HFCS, fructose, glucose or aspartame at the end of intervention. The specific objective of these studies is to test the hypothesis that 2 weeks of fructose or HFCS consumption will increase the absolute and proportional contributions of fatty acids derived from DNL to late-night increases of TRL, and that the increases of DNL-fatty acid will be a critical determinant of the increases of fasting LDL and ApoB concentrations. A second objective is to determine the doses of HFCS that increase the absolute and proportional contributions of DNL-fatty acids to postprandial TRL. PUBLIC HEALTH RELEVANCE: There is evidence to suggest that consumption of high sugar diets is associated with increased incidence of cardiovascular disease and diabetes, and the early results from the parent study indicate that consumption of beverages sweetened with high fructose corn syrup (HFCS) at 25% of energy requirement for 2 weeks increases risk factors for cardiovascular disease, including late-night triglyceride (TG) concentrations, and fasting LDL-cholesterol and apolipoprotein-B concentrations. Scientific evidence suggests that increased plasma TG concentrations after meals lead to the increases of other risk factors, and studies are proposed to mechanistically investigate the late-night postprandial increase of TG induced by consumption of HFCS and fructose. These studies will help to determine how sugar consumption may promote increased risk for cardiovascular and related metabolic diseases.
DE NOVO LIPOGENESIS IN THE PATHOGENESIS OF NON-ALCOHOLIC FATTY LIVER DISEASE
DESCRIPTION: Fatty liver - steatosis - affects about one third of the population. Its prevalence is rising and seems to parallel the global increase in obesity and type-2 diabetes. The mechanisms underlying steatosis and leading to non-alcoholic fatty liver disease are poorly understood. We propose that the hepatic conversion of carbohydrates (CHO) to lipids (de novo lipogenesis, DNL) is a key factor in the accumulation of excess liver fat and the accompanying dyslipidemia and that suppressing DNL by diet will reduce liver fat and improve the metabolic profile in patients with steatosis. These hypotheses are based on studies in which we and others have established that fractional hepatic DNL can vary dramatically depending on the diet and/or health status of a subject; and, in particular, that dietary fructose is a potent lipogenic stimulus. In this proposal we will perform Clinical Research Center (CRC) based studies to compare the rates of DNL and VLDL kinetics in steatotic and matched non-steatotic controls and evaluate their relationship to lipid profiles (Aim 1). The steatotic individuals whose habitual intake of fructose and other simple sugars exceeds 15% of total energy intake will then be randomized to consume one of two low-fat diets that differ only in CHO type to determine whether diet-induced changes in DNL affect liver fat flux, content (Aim 2). We hypothesize that a diet that is rich in complex CHO will achieve greater decreases in DNL and liver fat than one that contains typical amounts of simple CHO, including fructose. This dietary intervention study includes a 6-week 25% energy restriction outpatient phase to promote moderate weight loss and improve insulin sensitivity, followed by a week weight maintenance with the last 5 days as an inpatient stay during which all of the studies performed at baseline (Aim 1) will be repeated. State-of-the-art stable isotope techniques will be used to assess hepatic DNL, apoB100 turnover, VLDL-TG fluxes, and lipolysis under fasting and fed conditions. Liver fat will be measured by proton magnetic resonance spectroscopy. These studies will allow us to evaluate the importance of DNL as a mechanism modulating liver fat content and flux, and the significance of CHO quality in dietary guidance for steatotic patients.
METABOLIC IMPACT OF FRUCTOSE RESTRICTION IN OBESE CHILDREN
The past 30 years have seen a dramatic increase in the proportion of children with from obesity, diabetes, and metabolic syndrome, which drive up health care costs and contribute to premature mortality. The etiology(ies) of metabolic syndrome remain(s) unknown. The racial/ethnic presentations of metabolic syndrome differ, especially in children. Obese Latino children exhibit the highest prevalence of dyslipidemia, visceral adiposity, and non-alcoholic fatty liver disease (NAFLD); African American children present instead with hypertension, worsened insulin resistance, and glucose intolerance. Understanding these variations in presentation of metabolic syndrome holds the key to understanding its pathogenesis and, therefore, its prevention and treatment. Evidence for both genetic and environmental differences in symptom prevalence abound, and suggest a gene/race-diet interaction. One likely contributor to the etiology of metabolic syndrome is fructose. The secular trend in fructose consumption parallels the triple epidemics of obesity, type 2 diabetes, and metabolic syndrome in children. Fructose stimulates hepatic de novo lipogenesis, which we have demonstrated contributes to dyslipidemia and NAFLD; and hepatic uric acid synthesis, thought to be important in hypertension. We hypothesize that racial/ethnic differences in fructose metabolism contribute to the observed racial/ethnic differences in presentation of the metabolic syndrome: that in Latinos, fructose is primarily converted to TG by DNL, which leads to an increase in liver fat content, VLDL-TG output, and TG levels; but in African Americans, a greater proportion of fructose is converted to glucose, which leads to increased glycemia and insulin resistance. We further hypothesize that 10 days of isocaloric fructose restriction will decrease DNL and IHL and improve lipid profiles in Latinos; and improve glucose control, insulin sensitivity, and blood pressure in African Americans. We will examine insulin sensitivity and glucose disposal (by OGTT), de novo lipogenesis and triglyceride-rich lipoprotein kinetics (by stable isotope measurement), lipid partitioning within tissues (by magnetic resonance spectroscopy), and nitric oxide metabolites (by HLPC and ELISA) in children with metabolic syndrome, stratified by race and gender; and then again after 10 days fructose restriction. We anticipate that comorbidities will improve in a race/ethnic specific fashion. The results of this study will have immediate impact on: 1) reasons for racial/ethnic differences in insulin resistance and obesity; 2) alterations of nutritional information and the Food Pyramid; 3) public health efforts regarding prevention and treatment of obesity, diabetes, and metabolic syndrome around the world; and 4) the regulation of food industry claims and food advertising.
- Schwarz J-M, Schutz Y, Froidevaux F, Acheson KJ, Jeanpretre N, Schneider H, Felber JP, Jequier E. Thermogenesis in men and women induced by fructose vs glucose added to a meal. Am J Clin Nutr 49:667-674, 1989.
- Schwarz J-M, Schutz Y, Piolino V, Schneider H, Felber JP, Jéquier E. Thermogenesis in obese women. effect of fructose vs glucose added to a meal. Am J Physiol 262:E394-E401, 1992.
- Schwarz J-M, Acheson KJ, Tappy L, Piolino V, Muller MJ, Felber JP, Jéquier E. Thermogenesis mechanisms and fructose metabolism in humans. Am J Physiol 262:E591-E598, 1992.
- Hellerstein MK, Neese RA, Schwarz J-M. Model for measuring absolute rates of hepatic de novo lipogenesis and re-esterification of free fatty acids. Am J Physiol 265:E814-E820, 1993.
- Romijn, JA, Chinkes D, Schwarz J-M, Wolfe RR. Lactate-pyruvate interconversion in blood: implications for in vivo tracer studies. Am J Physiol 266:E334-E340, 1994.
- Hellerstein MK, Benowitz NL, Neese RN, Schwarz J-M, Hoh R, Jacob P, Hsieh J, Faix D. Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers. J Clin Invest 93:265-272, 1994.
- Schwarz J-M, Neese RA, Dare D, Turner SM, Hellerstein MK. Short-term alterations in carbohydrate energy intake in humans. J Clin Invest 96:2735-2743, 1995.
- Neese RA, Schwarz J-M, Faix D, Turner S, Letscher A, Vu D, Hellerstein MK. Gluconeogenesis and intrahepatic triose phosphate flux in response to fasting or substrate loads. J Biol Chem 270(24):14452, 1995.
- Hellerstein MK, Neese RA, Schwarz J-M, Turner S, Faix D, Wu K. Altered fluxes responsible for reduced hepatic glucose production and gluconeogenesis by exogenous glucose in rats. Am J Physiol 272:E163-E172, 1997.
- Gastaldelli A, Schwarz J-M, Caveggion E, Traber L, Traber D, Rosenblatt J, Toffolo G, Cobelli C, Wolfe R. Modeling in physiology: Glucose kinetics in interstitial fluid can be predicted by compartmental modeling. Am J Physiol 272:E494-E505, 1997.
- Tappy L, Schwarz J-M, Schneiter P, Cayeux C, Revelly,J-P, Fagerquist CF, Jequier E, Chiolero R. Effects of isoenergetic glucose-based or lipid-based parenteral nutrition on glucose metabolism, de novo lipogenesis, and respiratory gas exchanges in critically ill patient. Crit Care Med 26 (5):860-867, 1998.
- Fagerquist CK, Schwarz J-M. Gas-phase acid/base chemistry and its effects on mass isotopomer abundance measurements of biomolecular ions. J Mass Spectrom 33:144-153, 1998.
- Tappy L, Berger M, Schwarz JM, McCamish M, Revelly JP, Schneiter P, Jequier E, Chiolero R. Hepatic and peripheral glucose metabolism in intensive care patients receiving continuous high- or low-carbohydrate enteral nutrition. JPEN 23:260-268, 1999.
- Schwarz J-M, Chiolero R, Revelly J-P, Cayeux C, Schneiter P, Jequier E, Chen T, Tappy L. Effects of enteral carbohydrates on de novo lipogenesis in critically ill patients. Am J of Clin Nutr 72:940-945, 2000.
- Loe YC, Bergeron N, Rodriguez N, Schwarz J-M. A gas chromatography mass spectrometry method to quantify blood hydroxycitrate concentration. Anal Biochem 292: 148-154, 2001.
- Noor M, Lo JC, Mulligan K, Schwarz J-M, Halvorsen R, Schambelan M, Grunfeld C. Metabolic effects of indinavir in healthy HIV seronegative men. AIDS 15:F11-F18, 4, 2001.
- Battilana P, Ornstein K, Minehira K, Schwarz J-M, Acheson K, Schneiter P, Burri J, Jequier E, Tappy L. Mechanisms of action of ß-glucan in postprandial glucose metabolism in healthy men. Eur J Clin Nutr 55 (5): 327-333, 2001.
- Lo JC, Mulligan K, Noor M, Schwarz J-M, Halvorsen RA, Grunfeld C, Schambelan M. The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 86:3480-3487, 2001.
- Minehira K, Novel-Chate V, Schwarz J-M, Gillet M, Darioli R, Chiolero R, Tappy L. Hepatic de novo lipogenesis after liver transplantation. JPEN 25:229-235, 2001.
- Noor M, Lo JC, Mulligan K, Schwarz J-M, Halvorsen R, Schambelan M, Grunfeld C.
- Metabolic effects of indinavir in healthy HIV seronegative men. AIDS 15: F11-F18, 2001.
- Schwarz J-M, Mulligan K, Lee J, Lo JC, Noor M, Wen M, Grunfeld C, Schambelan M. The effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 87: 942-945, 2002.
- Trimmer JK, Schwarz JM, Casazza GA, Horning MA, Rodriguez N, Brooks GA. Measurement of gluconeogenesis in exercising men by mass isotopomer distribution analysis. J Appl Physiol 2002 93:233-241, 2002.
- Noor MA, Seneviratne T, Aweeka F, Lo JC, Schwarz J-M, Mulligan K, Schambelan M, Grunfeld C. The HIV protease inhibitor indinavir acutely inhibits insulin-stimulated glucose disposal. A randomized, placebo-controlled study. AIDS 16:F1-F8, 2002.
- Minehira K, Tappy L, Chioléro R, Vladomira V, Berger MM, Revelly J-P, Schwarz J-M. Fractional hepatic de novo lipogenesis in healthy subjects during near-continuous oral nutrition and bed rest. A comparison with published data in artificially fed, critically ill patients. Clin Nutr 21: 345-350, 2002.
- Schwarz J-M, Linfoot PA, Dare D, Aghajanian K. Hepatic de novo lipogenesis in normo and hyperinsulinemic subjects consuming high-fat/low-carbohydrate and low-fat/high-carbohydrate isoenergetic diets. Am J Clin Nutr 77: 43-50, 2003.
- Lee G, Seneviratne T, Noor MA, Lo JC, Schwarz J-M, Aweeka FT, Mulligan K, Schambelan M, Grunfeld C. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS 18:641-649, 2004.
- Lee GA, Mafong DD, Noor MA, Lo JC, Mulligan K, Schwarz J-M, Schambelan M, Grunfeld C. HIV protease inhibitors increase adiponectin in HIV-negative men. J Acquir Immune Defic Syndr 36:645-647, 2004.
- Lo JC, Mulligan K, Noor MA, Lee GA, Schwarz J-M, Grunfeld C, Schambelan M. The effects of low dose growth hormone in HIV-infected men with fat accumulation: a pilot study. Clin Infect Dis 39:732-735, 2004.
- Schwarz J-M, Lee GA, Park S, Noor MN, Lee J, Wen M, Lo JC, Mulligan K, Schambelan M, Grunfeld C. Indinavir increases glucose production in healthy HIV-negative men. AIDS 18:1852-1854, 2004.
- Faeh D, Minehira K, Schwarz J-M, Periasamy R, Park S, Tappy L. Effect of fructose supplementation and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy males. Diabetes 54:1907-1913, 2005.
- Tappy L, Berger MM, Schwarz J-M, Schneiter P, Kim S, Revelly JP, Chiolero R. Metabolic effects of parenteral nutrition enriched with n-3 PUFA acids in critically ill patients. Clin Nut 25(4):588-95, 2006.
- Lee GA, Mafong DD, Lo JC, Schwarz J-M, Aweeka FT, Mulligan K, Schambelan M, Grunfeld C. Single-dose lopinavir/ritonavir acutely inhibits insulin-mediated glucose disposal in healthy normal volunteers. Clin Infect Dis.; 43: 658-660, 2006.
- Lee GA, M Rao, K Mulligan, JC Lo, F Aweeka, J-M Schwarz, M Schambelan, and C Grunfeld. Effects of Ritonavir and Amprenavir on Insulin Sensitivity in Healthy Volunteers. AIDS 21(16):2183-90, 2007.
- Mulligan K, Khatami H, Schwarz J-M, Sakkas GK, DePaoli AM, Tai VW, Wen MJ, Lee GA, Grunfeld C, Schambelan M. The effects of recombinant human leptin on visceral fat, dyslipidemia, and insulin resistance in patients with HIV-associated lipoatrophy and hypoleptinemia. J Clin Endocrinol Metab 94:1137-1144, 2009.
- K Stanhope#, Schwarz# J-M, NL Keim, SC Griffen, AA Bremer, JL Graham, B Hatcher, CL Cox, A Dyachenko, J cGahan, A Seibert, RM Krauss, S Chiu, EJ Schaefer, M Ai, S Otokozawa, K Nakajima, T Nakano, C Beysen, MK Hellerstein, L Berglund, PJ Havel. Effects of consuming fructose- or glucose-sweetened beverages for 10 weeks on lipids, insulin sensitivity and adiposity. J Clin Invest 119(5):1322-34 2009 (# co–first authors).
- Lee GA, Schwarz J-M, Patzek S, Kim S, Dyachenko A, Wen M, Mulligan K, Schambelan M, Grunfeld C. The Acute Effects of HIV Protease Inhibitors on Insulin Suppression of Glucose Production in Healthy HIV-Negative Men. J Acquir Immune Defic Syndr 52(2):246-8, 2009.
- Pao VY, Lee GA, Taylor S, Aweeka FT, Schwarz J-M, Mulligan K, Schambelan M, Grunfeld C. The protease inhibitor combination lopinavir/ritonavir does not decrease insulin secretion in healthy, HIV-seronegative volunteers. AIDS 24(2):265-70, 2010.
- Campos GM, Rabl C, Peeva S, Ciovica R, Rao M, Schwarz J-M, Havel P, Schambelan M, Mulligan K. Improvement in Peripheral Glucose Uptake After Gastric Bypass Surgery Is Observed Only After Substantial Weight Loss Has Occurred and Correlates with the Magnitude of Weight Lost. J Gastrointest Surg. 14(1):15-23, 2010.
- Lim JS, Mietus-Snyder M, Valente A, Schwarz J-M, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 7 (5):251-6, 2010.
- Pasarica M, Rood J, Ravussin E, Schwarz J-M, Smith SR, Redman LM. Reduced Oxygenation in Human Obese Adipose Tissue Is Associated with Impaired Insulin Suppression of Lipolysis. J Clin Endocrinol Metab 95(8); 4052-5 2010.
- Rao MN, Mulligan K, Tai V; Wen, MJ; Dyachenko A, Weinberg M, Li X, Lang T; Grunfeld C, Schwarz J-M, Schambelan M. Effects of insulin-like growth factor (IGF)-I/IGF-binding protein-3 treatment on glucose metabolism and fat distribution in human immunodeficiency virus-infected patients with abdominal obesity and insulin resistance. J Clin Endocrinol Metab 95(9): 4361-6, 2010.
- Taylor SA, Lee GA, Pao VY, Anthonypillai J, Aweeka FT; Schwarz J-M; Mulligan K, Schambelan M, Grunfeld C. Boosting dose ritonavir does not alter peripheral insulin sensitivity in healthy HIV-seronegative volunteers. J Acquir Immune Defic Syndr 55(3): 361-4, 2010.
- Smith TJ, Schwarz J-M, Montain SJ, Rood J, Pikosky MA, Castaneda-Sceppa C, Glickman E, Young AJ. High protein diet maintains glucose production during exercise-induced energy deficit: a controlled trial. Nutr Metab (Lond). 28;8:26, 2011.
- Stanhope KL, Griffen SC, Bremer AA, Vink RG, Schaefer EJ, Nakajima K, Schwarz J-M, Beysen C, Berglund L, Keim NL, Havel PJ. Metabolic responses to prolonged consumption of glucose- and fructose-sweetened beverages are not associated with postprandial or 24-h glucose and insulin excursions. Am J Clin Nutr. 94(1):112-9, 2011.
- Cox CL, Stanhope KL, Schwarz J-M, Graham JL, Hatcher B, Griffen SC, Bremer AA, Berglund L, McGahan JP, Keim NL, Havel PJ. Circulating concentrations of monocyte chemoattractant protein-1, plasminogen activator inhibitor-1, and soluble leukocyte adhesion molecule-1 in overweight/obese men and women consuming fructose- or glucose-sweetened beverages for 10 weeks. J Clin Endocrinol Metab. 96(12): E2034-8, 2011.
- Cox CL, Stanhope KL, Schwarz J-M, Graham JL, Hatcher B, Griffen SC, Bremer AA, Berglund L, McGahan JP, Havel PJ, Keim NL.Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women. Eur J Clin Nutr. 66(2):201-8, 2012.
1985-1989 Scholarship Xyrofin Ltd.
1989 International Foundation for the Promotion of Nutrition Research and Nutrition Education
1992 Fonds National Suisse de la Recherche Scientifique
1993 Fondation Suisse de Bourses en Médecine et Biologie
1995 Mead Johnson Research Fund
1997 American Heart Association Investigator Development Award
|Employer||Title||From - To|
|Lausanne University, Switzerland||Research Assistant||1985-1989|
|University of Texas Medical Branch, Galveston Texas||Post-doctoral Fellow||1990-1992|
|University of California, Berkeley||Post-doctoral Fellow||1992-1994|
|University of California, Berkeley, Department of Nutritional Sciences||Assistant Professor||1995-2003|
|University of California San Francisco, Department of Medicine||Adjunct Assistant Professor||1999-2003|
|Touro University, School of Osteopathic Medicine Vallejo, CA||Associate Professor||2004-2008|
|University of California San Francisco, Department of Medicine||Associate Research Endocrinologist||2004-present|
|Touro University, School of Osteopathic Medicine Vallejo, CA||Professor||2008-present|
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