Malcolm Watford, D.Phil.

Professor of Nutritional Sciences & director, George H. cook scholars program, Rutgers

Post-doc, Case Western Reserve University, Cleveland, OH
Post-doc, Universite de Montreal, Montreal, Canada
D. Phil., Oxford University, U.K. 1977
B.Sc., Trent Polytechnic, Nottingham, U.K.

Specific Research Areas:

  1. My laboratory focuses on the role of amino acids (notably glutamine and glutamate) as substrates for gluconeogenesis and urea synthesis.  This encompasses work in vitro and in vivo using cells and tissues from many different organs, as well as the use, to date, of thirteen different species. (I am a great believer in the August Krogh principle, “for many problems in physiology there is an animal on which it can most conveniently be studied.”)

    Tissue-specific glutamine metabolism
    I have studied glutamine metabolism in liver, kidney, intestine, skeletal and cardiac muscle, adipose and tissue, immune cells, as well as the lactating mammary gland, and placental and fetal tissues during gestation.  We were the first to isolate metabolically viable enterocytes from the rat and to identify and quantitate the major end products of glucose, glutamate and glutamine metabolism in such cells.   We developed the first microdialysis and arterio-venous difference techniques to quantify metabolic flux in rat adipose tissue in vivo and established that rat adipose tissue is a site of net glutamine production.  We recently established that adipocyte glutamine synthetase is involved in the adipocyte remodeling that occurs in obesity and that adipocytes can provide the glutamine that is essential to macrophage survival.  We are continuing these studies with the ultimate aim of defining the role of adipocyte glutamine synthesis in development of insulin resistance and Type 2 diabetes mellitus.

    Regulation of phosphate activated glutaminase and glutamine synthetase  
    My group demonstrated that hepatic (liver-type) glutaminase was subject to long-term hormonal and dietary regulation.  We were then the first to purify liver-type glutaminase, raise antibodies to the protein and isolate, and sequence, both cDNA and genomic clones.  Using these tools we demonstrated that hormonal and dietary regulation occurred at the level of transcription and identified the upstream enhancer sequences involved.  (Note: This gene and protein have been renamed, Gls2, and is currently the focus of extensive investigation in tumor biology).  For many years we have also studied the opposing enzyme, glutamine synthetase and have identified how this enzyme is regulated by glutamine induced proteolysis via the ubiquitin linked proteasome.  We continue to study the role of this enzyme in adipocyte differentiation (qv), and also in the provision of milk glutamine.

    Glutamine supplementation in lactation
    Glutamine and glutamate are the most abundant amino acids in milk.  We established that lactation in is  accompanied by a net catabolic state and loss of lean body mass, caused, in part, by the need to provide glutamine in the milk.  We recently showed that glutamine and glutamate supplementation to the diet can both prevent the loss of lean body mass during lactation and also increase the glutamine content of milk.  We are extending this work to the study of amino acid metabolism during lactation and the role of different tissues in the provision of milk glutamine and glutamate. 

    Glutamine metabolism in uricotelic species
    One of my long standing interests is the comparative biochemistry/physiology of nitrogen excretion.  To this end we have carried out extensive studies of uric acid production in species such as birds and lizards.  

    Outstanding theoretical questions
    I am continuously searching for ways to address the following questions (but the answers are far from obvious and certainly not easy to test experimentally):

    1. Why do rapidly dividing and differentiating cells require the catabolism of extremely large amounts of glutamine?
    2. Are glutamine and glutamate dispensable or indispensable in the diet?

Representative Publications

  • Watford, M., Lund, P. and Krebs, H.A. (1979) Isolation and Metabolic Characterization of Rat and Chicken Enterocytes.  Biochem. J. 178: 589-596
  • Watford, M., Vinay, P., Lemieux, G. and Gougoux, A. (1980) The Regulation of Glucose and Pyruvate Formation from Glutamine and Citric Acid Cycle Intermediates in the Kidney Cortex of Rats, Dogs, Rabbits, and Guinea Pigs.  Biochem. J. 188: 741-748
  • Watford, M., Hod, Y., Chiao, Y.-B., Utter, M.F. and Hanson, R.W. (1981) The Unique Role of the Kidney in Gluconeogenesis in the Chicken:  The Significance of a Cytosolic Phosphoenolpyruvate Carboxykinase Activity.  J. Biol. Chem. 256:  10023-10027
  • Watford, M., Smith, E.M. and Erbelding, E.J. (1984) The Regulation of Phosphate Activated Glutaminase Activity and Glutamine Metabolism in the Streptozotocin-Diabetic Rat.  Biochem. J. 224: 207-214
  • Watford, M., Erbelding, E.J. and Smith, E.M. (1987)  The Regulation of Glutamine and Ketone Body Metabolism in the Small Intestine of the Long-term (40-day) Streptozotocin-Diabetic Rat.  Biochem. J. 242:  61-68
  • Smith, E.M. and Watford, M. (1988) Rat Hepatic Glutaminase:  Purification and Immunochemical Characterization.  Arch. Biochem. Biophys. 260: 740-751
  • Smith, E.M. and Watford, M. (1988) Rat Hepatic Glutaminase:  Purification and Immunochemical Characterization.  Arch. Biochem. Biophys. 260: 740-751
  • Watford, M. and Smith, E.M. (1990) Distribution of Hepatic Glutaminase Activity and mRNA in Perivenous and Periportal Rat Hepatocytes.  Biochem. J. 267: 265-267
  • Smith, E.M. and Watford, M. (1990) Molecular Cloning of a cDNA for Rat Hepatic Glutaminase:  Sequence Similarity to Kidney-type Glutaminase.  J. Biol. Chem. 265: 10631-10636
  • Kowalski, T.J. and Watford, M. (1994)  Production of Glutamine and Utilization of Glutamate by Rat Subcutaneous Adipose Tissue In Vivo.  Am. J. Physiol. 266: E151-E154
  • Watford, M. (1994)  Glutamine Metabolism in Rat Small Intestine.  Synthesis of Three-Carbon End Products in Isolated Enterocytes.  Biochim. Biophys. Acta 1200: 73-78
  • Zhan, Z., Vincent, N., and Watford, M. (1994) Transcriptional Regulation of the Hepatic Glutaminase Gene in the Streptozotocin-Diabetic Rat.  Int. J. Biochem. 26: 263-268
  • Watford, M., Vincent, N., Zhan, Z., Fanelli, J., Kowalski, T.J. and Kovacevic, Z. (1994) Transcriptional Regulation of Rat Hepatic Glutaminase Expression by Dietary Protein Level and Starvation.  J. Nutr. 124: 493-499
  • Curthoys, N.P. and Watford, M. (1995) Regulation of Glutaminase Expression and Glutamine Metabolism.  Ann. Rev. Nutr. 15: 133-159
  • Chung-Bok, M.I., Vincent, N., Jhala, U. and Watford, M. (1997)  Rat Liver Glutaminase:  Identification of the Full-Length Coding Sequence and Characterization of a Functional Promoter.  Biochem. J. 324: 193-200
  • Kowalski, T.J., Wu, G. and Watford, M. (1997) Rat Adipose Tissue Amino Acid Metabolism In Vivo as Assessed by Microdialysis and Arterio-Venous Techniques.  Am. J. Physiol. 273: E613-E622
  • Wu, G., Chung-Bok, M.-I., Vincent, N., Kowalski, T.J., Choi, Y-H. and Watford, M. (1998) Distribution of Phosphate Activated Glutaminase Isozymes in the Chicken:  Absence from Liver but Presence of High Activity in Pectoralis Muscle.  Comp. Biochem. Physiol. 120B, 285-290
  • Watford, M and Wu, G. (2005) Glutamine metabolism in uricotelic species: variation in skeletal muscle glutamine synthetase, glutaminase, glutamine content and rates of protein synthesis.  Comp. Biochem. Physiol. 140B, 607-614
  • Wang, Y. and Watford, M. (2007) Glutamine, insulin and glucocorticoids regulate glutamine synthetase expression in C2C12 myotubes, HepG2 hepatoma cells and 3T3 L1 adipocytes.  Biochim. Biophys. Acta 1770: 594-600
  • Huang, Y.-F., Wang, Y. and Watford, M. (2007) Glutamine directly down-regulates the level of glutamine synthetase protein in C2C12 skeletal muscle cells. J. Nutr. 137: 1357-136
  • Watford, M. (2008) Glutamine metabolism and function in relation to proline synthesis and the safety of glutamine and proline supplementation. J. Nutr.  138: 2003S-2007S
  • Manso-Filho, H.C., McKeever, K.H., Gordon, M.E., Lagakos, W., Costa, H.E.C.and Watford, M. (2008) Changes in glutamine metabolism indicate a mild catabolic state in the transition mare.  J. Animal Sci. 86: 3424-3431
  • Treberg, J., Brosnan, M.E., Watford, M. and Brosnan, J.T.  (2010) On the reversibility of glutamate dehydrogenase and the source of ammonia in the hyperinsulinemia/hyperammonenia syndrome. Adv. Enz. Reg. 50, 34-43
  • Fang, Q., Yin, J,, Li, F., Zhang, J. and Watford, M. (2010) Characterization of expression of Methionine Adenosyltransferase 2b gene in skeletal muscle and subcutaneous adipose tissue from obese and lean pigs. Mol. Biol. Reports 37: 2517-2524
  • Watford, M. and Wu, G. (2011) Protein,  Advances in Nutrition 2: 62-64
  • Watford, M., Kutschenko, M. and Nogueira, E.T. (2011) Optimal dietary glutamine for growth and development, Revista Brasileira de Zootecnia 40, 384-390
  • Manso, H.E., Manso Filho, H.C., de Carvalho, L.E. and Watford, M. (2012) Glutamine and glutamate supplementation maintain skeletal muscle glutamine concentrations and raise milk glutamine content in gilts.  J. Animal Sci. Biotechnol 3(1):2. doi: 10.1186/2049-1891-3-2.
  • Santos de Aquino, R., Dutra, W.M., Manso, H.E.C.C., Manso Filho, H.C., Kutschenko, M., Nogueira, E.T. and Watford, M. (2014) Glutamine and glutamate (AminoGut) supplementation influences sow colostrum and mature milk composition.  LiveStock Science,169: 112-117
  • Watford, M. and Brosnan, J.T. (2014) Hans Krebs and the foundation of the use of glutamine in clinical nutrition: A personal perspective. Chinese Journal of Clinical Nutrition (published in Chinese, Hans Krebs与谷氨酰胺在临床营养中的应用) 22:1-8
  • Watford, M. (2015) Starvation: Metabolic Changes.  In Encyclopedia of Life Sciences (John Wiley & Sons Ltd. Chichester) DOI: 10.1002/9780470015902.a0000642.pub2
  • Watford, M and Castell, L.M. (2015) Proline,in Nutritional Supplements in sport, exercise and health: An A-Z guide.  L.M. Castell, S.J. Stear, L.M. Burke, eds. Routledge, Taylor and Francis, London & New York, page 219
  • Wang, S., Thacker, P.A., Watford, M., Qiao, S. (2015) Functions of antimicrobial peptides in gut homeostasis.  Curr. Prot. Pept. Sci.  published on line July 2015
  • Duan, Y., Li, F., Li, Y., Tang, Y., Liu, Y., Liu, H., Feng, Z., Anthony, T.G., Watford, M. and Yin, Y.  (2015) Potential role of leucine and its metabolites in protein metabolism and energy production of human and animals.  Amino Acids, in press
  • Watford, M. (2015) Glutamine and glutamate:  Nonessential or essential amino acids?  Animal Nutrition, in press