Education

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Employment History

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Teaching

Fall Semester
PA 600: Basic Science Foundations (Course Director)

Spring Semester
PA617: Clinical Medicine III (Participating Faculty Member)
OMS program Elective (Participating Faculty Member)

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Research Interests

Mass Spectrometry Lab

Most often, the disorders of carbohydrate (CHO) and fat metabolism have been studied independently, and the importance of their mutual interaction has been overlooked. My interest in the inter-relationship between CHO and fat metabolism was triggered by the fact that, although individuals with insulin resistance and type 2 diabetes are identified and treated for their problems with CHO homeostasis, they often have equally important perturbations of fat homeostasis (dyslipidemia) and are more likely to die from cardiovascular diseases. For these reasons, I have spent the past twelve years concentrating my research efforts on whole body and hepatic fuel homeostasis with special attention to the inter-relationship between carbohydrate and fat metabolism.

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.

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Honors & Awards

Year Recognition
1985 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 Biologi
1995 Mead Johnson Research Fund
1997 American Heart Association Invest. Development Award

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Publications

1. Schwarz JM; Y Schutz; F Froidevaux; KJ Acheson ; N Jeanpretre; H Schneider; JP Felber; and E Jequier: Thermogenesis in men and women induced by fructose vs glucose added to a meal. Am J of Clin Nutr 49(4):667-74, 1989.
2. Schwarz JM, Y Schutz, V Piolino, H Schneider, JP Felber and E Jéquier: Thermogenesis in obese women: effect of fructose vs glucose added to a meal. Am J Physiol 262:E394-E401, 1992.
3. Schwarz JM, KJ Acheson, L Tappy, V Piolino, MJ Muller, JP Felber and E Jéquier: Thermogenesis mechanisms and fructose metabolism in humans. Am J Physiol 262:E591-E598, 1992.
4. Hellerstein MK, RA Neese, and JM Schwarz: Model for measuring absolute rates of hepatic de novo lipogenesis and re-esterification of free fatty acids. Am J Physiol 265:E814-E820, 1993.
5. Romijn, JA, D Chinkes, JM Schwarz, and RR Wolfe: Lactate-pyruvate interconversion in blood: implications for in vivo tracer studies. Am J Physiol 266:E334-E340, 1994.
6. Hellerstein, MK, NL Benowitz, RN Neese, JM Schwarz, R Hoh, P Jacob, J Hsieh and D Faix: Effects of cigarette smoking and its cessation on lipid metabolism and energy expenditure in heavy smokers. J Clin Invest 93:265-272, 1994.
7. Schwarz JM, RA Neese, D Dare, SM Turner, and MK Hellerstein: Short-term alterations in carbohydrate energy intake in humans. J Clin Invest 96:2735-2743, 1995.
8. Neese RA, JM Schwarz, D Faix, S Turner, A Letscher, D Vu and MK Hellerstein: Gluconeogenesis and intrahepatic triose phosphate flux in response to fasting or substrate loads. J Biol Chem 270(24):14452, 1995.
9. Hellerstein MK, A Letcher, JM Schwarz, D Cesar, CHL Schackleton, S Turner, RA Neese, K Wu, S Block, and S Kaempfer: Measurement of rate of appearance of hepatic UDP-glucose in vivo in rats: relation to glycogen deposition and labeling patterns. Am J Physiol 272:E155-E162, 1997.
10. Hellerstein MK, RA Neese, JM Schwarz, S Turner, D Faix , and K Wu: Altered fulxes responsible for reduced hepatic glucose production and gluconeogenesis by exogenous glucose in rats. Am J Physiol 272:E163-E172, 1997.
11. Gastaldelli, A, JM Schwarz, E Caveggion, , L Traber, D Traber, J Rosenblatt, G Toffolo, C Cobelli and R Wolfe: Modeling in physiology: Glucose kinetics in interstitial fluid can be predicted by compartmental modeling. Am J Physiol 272:E494-E505, 1997.
12. Tappy L, JM Schwarz, P Schneiter, C Cayeux, J-P Revelly, CF Fagerquist, E Jequier, and R Chiolero: 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.
13. Fagerquist CK and JM Schwarz: Gas-phase acid/base chemistry and it’s effects on mass isotopomer abundance measurements of biomolecular ions. J Mass Spectrom 33:144-153, 1998.
14. Tappy L, MM Berger, JM Schwarz, M McCamish, J-P Revelly, P Schneiter, E. Jequier and R Chiolero: Hepatic and peripheral glucose metabolism in intensive care patients receiving continuous high or low carbohydrate enteral nutrition. Jpen-Parenter Enter 23: 260-268, 1999.
15. Schwarz JM, R Chiolero, J-P Revelly, C Cayeux, P Schneiter, E Jequier, T Chen, and L Tappy: Effects of enteral carbohydrates on de novo lipogenesis in critically ill patients. Am J of Clin Nutr. 72(4):940-5, 2000
16. Loe YC, N Bergeron, N Rodriguez, and JM Schwarz. A gas chromatography mass spectrometry method to quantify blood hydroxycitrate concentration. Anal Biochem 292 (1): 148-154 2001.
17. Noor M, JC Lo, K Mulligan, JM Schwarz, R Halvorsen, M Schambelan, and C Grunfeld. Metabolic effects of indinavir in healthy HIV seronegative men. Aids 15 (7): F11-F18, 4 2001
18. Battilana P, K Ornstein, K Minehira, JM Schwarz, K Acheson, P Schneiter, J Burri, E Jequier, and L Tappy. Mechanisms of action of ß-glucan in postprandial glucose metabolism in healthy men. Eur J Clin Nutr 55 (5): 327-333, 2001.
19. Lo JC, K Mulligan, M Noor, JM Schwarz, RA Halvorsen, C Grunfeld, and M Schambelan. The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 86:3480-87, 2001.
20. Minehira K, V Novel-Chaté, JM Schwarz, M Gillet, R Darioli, R Chioléro, and L Tappy. Hepatic de novo lipogenesis after liver transplantation. J Parenter Enter Nutr 25:229-235, 2001.
21. Schwarz JM, K Mulligan, J Lee, JC Lo, M Noor, M Wen, C Grunfeld, and M Schambelan. 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(2): 942-945, 2002.
22. Trimmer JK, JM Schwarz, GA Casazza, MA Horning, N Rodriguez, and GA Brooks. Measurement of gluconeogenesis in resting and exercising men by mass isotopomer distribution analysis (MIDA) J Appl Physiol 93: 233-241, 2002.
23. Noor MA, T Seneviratne, F Aweeka, JC Lo, JM Schwarz, K Mulligan, M Schambelan, and C Grunfeld. The HIV protease inhibitor indinavir acutely inhibits insulin-stimulated glucose disposal: A randomized, placebo-controlled study. AIDS 16(5):F1-F8, 2002.
24. Minehira K, L. Tappy, R Chioléro V Vladomira, MM Berger, J-P Revelly, and JM Schwarz. 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 (4): 345-350, 2002.
25. Schwarz JM, PA Linfoot, D Dare, and K Aghajanian. Hepatic de novo lipogenesis in normo and hyperinsulinemic subjects consuming high-fat/low-carbohydrate and low-fat/high-carbohydrate isoenergetic diets Am J of Clin Nutr 77 (1): 43-50, 2003.
26. Lee G, T Seneviratne, MA Noor, JC Lo, JM Schwarz, FT Aweeka, K Mulligan, M Schambelan, and C Grunfeld. The metabolic effects of lopinavir/ritonavir in HIV-negative men. AIDS 18:641-649, 2004.
27. Lee GA, DD Mafong, MA Noor, JC Lo, K Mulligan, JM Schwarz, M Schambelan, and C Grunfeld. HIV Protease inhibitors increase adiponectin levels in HIV-negative men. J Acquire Immune Defic Syndr 36:645-647, 2004.
28. Lo JC, K Mulligan, MA Noor, GA Lee, JM Schwarz, C Grunfeld, and M Schambelan. The effects of low dose growth hormone in HIV-infected men with fat accumulation: a pilot study. Clin Infect Dis. 39(5):732-5, 2004.
29. Schwarz JM, GA Lee, S Park, MN Noor, C Lee, M Wen, JC Lo, K Mulligan, M Schambelan, and C Grunfeld. Indinavir increases glucose production in healthy HIV-negative men. AIDS 18(13):1852-4, 2004.
30. Faeh D, K Minehira1, JM Schwarz, R Periasami, S Park, and L Tappy. Effect of fructose supplementation and fish oil administration on hepatic de novo lipogenesis and insulin sensitivity in healthy males. Diabetes 54:1907-1913, 2005.
31. Tappy L, MM Berger, JM Schwarz, P Schneiter, S Kim, JP Revelly, and R Chiolero. Metabolic effects of parenteral nutrition enriched with n-3 polyunsaturated fatty acids in critically ill patients. Clin Nutr.; 25(4):588-95, 2006.
32. Lee GA, DD Mafong, JC Lo, JM Schwarz, FT Aweeka, K Mulligan, M Schambelan, and C Grunfeld. Single-dose lopinavir/ritonavir acutely inhibits insulin-mediated glucose disposal in healthy normal volunteers. Clin Infect Dis. Clin Infect Dis: 43(5):658-60, 2006.
33. Lee GA, M Rao, K Mulligan, JC Lo, F Aweeka, JM Schwarz, M Schambelan, and C Grunfeld. Effects of Ritonavir and Amprenavir on Insulin Sensitivity in Healthy Volunteers. AIDS, 21(16):2183-90, 2007.

REVIEW and BOOK CHAPTER
Hellerstein MK, JM Schwarz, and RN Neese: Regulation of hepatic de novo lipogenesis in humans. Annual Review of Nutrition 16:523-57, 1996.
Tappy L and JM Schwarz. Metabolic Disorders. Clinical Nutrition, 5:76-84, 2005. The Nutrition Society Textbook Series. Published by Blackwell Science.

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Research Grants

Current


ABSTRACTS OF FUNDED GRANT

NIH/NIDDK 1R01DK078133-01A1 (PI: Schwarz, 1/09/2007-30/08/2011)

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 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 and 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. This will be followed by a 2-week weight maintenance with the last five 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.

AMERICAN DIABETES ASSOCIATION 1-08-CR-56 (PI: Schwarz, 1/1/2008-12/31/2010)

The prevalence of hepatic steatosis is rising and parallels the global increase in obesity and type-2 diabetes. We propose that increased hepatic carbohydrate (CHO) flux and CHO conversion to lipids (lipogenesis) are key factors in liver fat accumulation and insulin resistance in steatotic patients, and that a dietary intervention that reduces lipogenesis will improve insulin sensitivity.
We will perform 5-day inpatient studies in steatotic individuals and matched nonsteatotic controls to compare gluconeogenesis, endogenous glucose production, and hepatic glycogen flux and evaluate their relationship to hepatic lipogenesis and insulin resistance. Steatotics whose habitual intake of fructose and simple sugars exceeds 15% of total energy intake will then be randomized to one of two low-fat, energy-restricted diets that differ only in CHO type (complex vs. simple sugars, including fructose) to determine whether diet-induced changes in hepatic lipogenesis and fat content affect CHO flux and insulin sensitivity. After the dietary intervention, subjects will repeat the inpatient studies performed at baseline. We hypothesize that the diet rich in complex CHO will achieve greater decreases in liver fat and improvements in insulin sensitivity.
Hepatic and extra-hepatic insulin sensitivity and CHO flux will be measured under fasting and during hyperinsulinemic-euglycemic clamp conditions using state-of-the-art stable isotope techniques. Muscle and liver fat will be measured by proton magnetic resonance spectroscopy. These studies will evaluate hepatic CHO fluxes as a mechanism modulating liver fat content and insulin sensitivity, and the significance of CHO quality in dietary guidance for steatotic patients.

Other Projects

1. Effects of High Fructose Diet on Liver Fat Production and Accumulation (role PI).

The major goals of this project are to evaluate the effects of a high-fructose diet on hepatic lipid production and accumulation (see abstract attached).

2. De Novo Lipogenesis in the Pathogenesis of Non-Alcoholic Fatty Liver Disease (role PI).

The major goals of this project are to evaluate the effects of the reduction of fructose consumption in steatotic patients (see abstract attached).

3. Leptin Treatment of HIV-Associated Lipodystrophy (PI: Schambelan UCSF, role Co-PI).

The major goal of this project is to evaluate the effects of recombinant human leptin on insulin sensitivity, lipid and carbohydrate metabolism, and fat distribution in HIV-infected patients with lipodystrophy (paper in preparation).

4. Can IGF-I/IGFBP-3 Reverse Central Fat Accumulation? (PI: Schambelan UCSF, role Co-PI)

The major goal of this project is to evaluate the effects of recombinant human insulin-like growth factor-I, complexed to its major binding protein, on central fat and insulin sensitivity in HIV-infected patients with excess central fat accumulation.

5. HIV Antiretroviral Drugs and Glucose Metabolism (PI: Grunfeld UCSF, role Co-PI).

The major goal of this project is to evaluate metabolic effects of drug-specific and not class-specific with independent effects of protease inhibitors on glucose metabolism.

6. Hormones and TG/Lipoprotein Metabolism (PI: Havel, UC Davis, role Collaborator)

The goal is to investigate the mechanisms by which fructose consumption leads to increases of triglycerides and ApoB production using stable isotopes to assess lipogenesis and apoB kinetics.

7. Uridine Supplementation, Mitochondrial Function, and Glucose Metabolism in HIV (PI: Schambelan UCSF, role Co-PI).

The major goal of this project is to determine whether supplementation with uridine will improve insulin sensitivity and overall glucose metabolism in HIV-infected patients with evidence of insulin resistance and mitochondrial dysfunction.

8. Fat Cell Size and Overfeeding and Ectopic Fat (PI: Ravussin, LSU Pennington Biomedical Research CTR, role Co-PI).

The goal of this project is to test the hypothesis that inability of the adipose organ to expand to accommodate excess calories (impaired adipogenesis) results in adipose tissue hypertrophy, ectopic fat deposition and insulin resistance in muscle, liver and adipose in predisposed subjects.

Previous
NIH/CReFF GCRC: Effects of High Fructose Diet on Liver Fat Production and Accumulation 9/04-12/05
Role: Principal Investigator

R01 DK54615 NIH/NIDDK (PI: Mulligan): Metabolic Effects of Protease Inhibitors in HIV Disease 9/98-08/05
Role: Co-Investigator

American Diabetes Association (011770): Effect of Fish Oil on Hepatic Lipid and Carbohydrate Metabolism in Hyperinsulinemic Obese Subjects 1/00-12/03
Role: Principal Investigator

USDA NRI (99 35200 8605): Effect of Fish Oil on Hepatic Lipid and CHO Metabolism in Healthy Human Subjects. 12/01-11/02
Role: Principal Investigator

R01 DK45833 NIH/NIDDK(PI: Schambelan): Anabolic Therapies & Their Metabolic Effects in AIDS 12/97-05/04.
Role: Co-Investigator

American Heart Association: Inhibition of de novo lipogenesis: Effect on glucose and VLDL output 1/98-12/01
Role: Principal Investigator

ILSI: Modulation of Hepatic de novo Lipogenesis: Effect on Glucose and VLDL Output 7/98-6/00
Role: Role: Principal Investigator

Hewlett Packard Award #010625: Measurement of isotope ratio of polymers using HP’s 8/98-7/99.
Role: Principal Investigator

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