Melanie Gillingham, PhD

RESEARCH

The mitochondrial fatty acid β-oxidation (FAO) pathway is critical for survival during periods of fasting and for the maintenance of normal body weight and insulin sensitivity. We are interested in the effects of disorders in the FAO system on body weight regulation and insulin sensitivity. To date we have been investigating metabolic consequences of genetic disorders in the FAO pathway including inherited deficiency of very-long chain acyl CoA dehydrogenase (VLCAD), long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD)  and carnitine palmitoyltransferase type 1A (CPT1A) deficiencies. FAO disorders are inherited in an autosomal recessive manner and collectively have an incidence of 1:9000 live births. Infants with a FAO disorder typically present with hypoketotic hypoglycemia and Reye-like symptoms precipitated by fasting or illness.

The treatment for long-chain fatty acid oxidation disorders has been primarily with a modified diet including avoiding long periods of fasting, and frequent high carbohydrate meals. We have been investigating alternative nutritional approaches including fish oil supplements, medium-chain triglyceride supplements prior to exercise, and high protein diet low-fat diets on the outcomes and complications of these disorders.
 
Our current work is focused on the treatment of rare disorders in the FAO pathway. Our future goal is to learn from these disorders about the role of fatty acid oxidation in body weight regulation and the development of insulin resistance. Using a candidate gene approach, we plan to study this pathway in more common diseases such as morbid obesity and type 2 diabetes.
 

SELECT PUBLICATIONS

Gillingham MB, Purnell JQ, Jordan J, Stadler D, Haqq AM, Harding CO. Effects of higher dietary protein intake on energy balance and metabolic control in children with with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Molecular Genetics and Metabolism, 90:64-69, 2007.
 
Gillingham MB, Scott B, Elliott D, Harding CO. Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Molecular Genetics and Metabolism 89:58-63, 2006.
 
Harding CO, Gillingham MB, Hamman K, Clark H, Bird A, Koeberl DD. Complete correction of hyperphenylalanemia following liver-directed recombinant AAV2/8 vector-mediated gene therapy in murine phenylketonuria. Gene Therapy 13: 457-462, 2005.
 
Gillingham, MB, Weleber RG, Neuringer M, Connor WE, Mills M, Van calcar S, Verhoeve J, Wolff J, Harding CO. Effect of optimal dietary therapy upon visual function in children with long-chain 3-hydroxyacyl CoA dehydrogenase (LCHAD) and trifunctional protein (TFP) deficiency. Molecular Genetics and Metabolism 86:124-133, 2005.
 
Gillingham, MB, Connor WE, Matern, D, Rinaldo P, Burlingame T, Meeuws K, Harding, CO. Optimal Dietary Therapy of Long-Chain 3-Hydroxyacyl-CoA Dehydrogenase (LCHAD) Deficiency. Molecular Genetics and Metabolism. 79: 114-123, 2003.