Randall L. Mynatt


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Ph.D., University of Tennessee, Knoxville, TN, 1991, Nutrition Sciences


Dr. Mynatt has over 20 years of experience in the obesity and diabetes field with the primary research focus on lipid metabolism and insulin resistance. As Director of the Transgenic Core at PBRC, he has generated over 50 mouse transgenic/knockout lines. He is also Director of the Animal Models and Phenotyping Core for the Nutrition and Obesity Research Center (NORC) Grant and Head of the Integrative Biology Core for the Pennington Botanical Research Center (BRC) Grant, he has extensive experience not only generating mouse models but also in metabolically phenotyping them.

Much of his research focus is on lipid metabolism with specific interests in the regulation of fatty acid oxidation. L-carnitine plays a critical role in the shuttling of acyl moieties across mitochondrial membranes, and it has been speculated that carnitine supplementation would improve glucose disposal by reducing the cellular concentrations of long-chain acyl-CoAs (LC-CoA) and acetyl-CoA, which are potent inhibitors of glucose utilization.

Our investigations have found that dietary carnitine supplementation improved insulin sensitivity in three mouse models of impaired insulin action: aging, genetic diabetes, and high-fat feeding. Concomitant with the benefits of supplemental carnitine on insulin sensitivity were increases in the cellular export and excretion of lipotoxic metabolites.

Key to understanding the extent of the contribution of mitochondrial efflux fatty acids to the overall benefit of supplemental carnitine is the manipulation of carnitine acetyltransferase (CRAT) in mice. The reduction of CRAT activity in muscle led to a moderate increase in fat mass when mice were fed a high-fat diet. However, the Crat knockout mice had higher blood glucose values and were less responsive to insulin irrespective of diet, indicating that insulin resistance in these mice is not secondary to obesity and suggesting a direct role of CRAT in muscle for glucose homeostasis. These data support the role of CRAT as a key enzyme in mitochondrial energy homeostasis.

The correlations between intramyocellular lipid, decreased fatty acid oxidation and insulin resistance have led to the hypothesis that impaired fatty acid oxidation (FAO) causes accumulation of lipotoxic intermediates that inhibit muscle insulin signaling. Using a skeletal muscle-specific carnitine palmitoyltransferase-1 knockout model, we show that prolonged and severe mitochondrial FAO inhibition results in a myriad of diabetes risk factors (reduced physical activity, increased circulating nonesterified fatty acids, and increased intramyocellular lipids, diacylglycerols and ceramides), without inducing insulin resistance. Perhaps more importantly, inhibition of mitochondrial FAO also reprograms muscle metabolism, invoking mitochondrial biogenesis, compensatory peroxisomal fat oxidation, amino acid catabolism and resistance to obesity.

Research in this laboratory is supported by grants from the American Diabetes Association and the National Institutes of Health.


Selected publications related to recent carnitine-related research

1. Power RA, Hulver MW, Zhang JY, Dubois J, Marchand RM, Ilkayeva O, Muoio DM, and Mynatt RL. Carnitine Revisited: Potential use as Adjunctive Treatment in Diabetes. Diabetologia 50:824-832, 2007.

2. Muoio DM, Noland RC, Kovalik JP, Seiler SE, Davies MN, Debaisi KL, Ilkayeva OR, Stevens RD, Kheterpal I, Zhang J, Covington JD, Bajpeyi S, Ravussin E, Kraus W, Koves TR and Mynatt RL. Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility. Cell Metabolism 15:764-777, 2012. PMC3348515

3. Haynie KR, Vandanmagsar B, Wicks S, Zhang J, and Mynatt RL. Inhibition of Carnitine Palymitoyltransferase1b Induces Cardiac Hypertrophy and Mortality in Mice. Diabetes, Obesity and Metabolism, 16:757-760, 2014. PMC4057362

4. 3. Wicks S, Vandanmagsar B, Haynie KR, Fuller, SE, Stephens, JM, Zhang J, Noland RC, and Mynatt RL. Impaired mitochondrial fat oxidation induces metabolic reprogramming in muscle. PNAS 112:E3300-3309, 2015. PMC4485116

5. Vandanmagsar B, Wicks SE, Warfel JD, Dubuisson OS, Mendoza TM, Zhang J, Noland RC, and Mynatt RL. Impaired mitochondrial fat oxidation induces FGF21 in muscle. Cell Rep. 2016 May 24;15(8):1686-99. PMID: 27184848

Selected publications related to core-related research

1. Vandanmagsar B, Youm Y-H, Ravussin A, Galgani J, Stadler K, Mynatt RL, Ravussin E, Stephens JM, and Dixit VD. (2011) The NLRP3 Inflammasome Instigates Obesity-Induced inflammation and Insulin Resistance. Nature Medicine 17:179-188.

2. Begriche K, Levasseur PR, Zhang J, Rossi J, Skorupa D, Sold LA, Young B, Burris TP, Marks DL, Mynatt RL and Butler AA. (2011) Genetic dissection of the functions of the melanocortin-3 receptor, a seven-transmembrane G-protein-coupled receptor, suggests roles for central and peripheral receptors in energy homeostasis. Journal of Biological Chemistry 286:40771-40781. PMC3220494

3. Kumar KG, Trevaskis JL, Lam DD, Sutton GM, Koza RA, Chouljenko VN, Kousoulas KG, Rogers PM, Kesterson RA, Thearle M, Ferrante AW, Mynatt RL, Burris TP, Dong JZ, Haleem HA, Culler MD, Heisler LK, Stephens JM, and Butler AA. (2008) Identification of Adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metabolism, 8:468-48. PMC2746325

4. Anunciado-Koza RP, Zhang J, Bajpeyi S, Koza RA, Rogers RC, Cefalu WT, Mynatt RL, and Kozak LP. Inactivation of the mitochondrial carrier Slc25a25 (ATP-Mg++/Pi transporter) increases metabolic inefficiency. Journal of Biological Chemistry 286: 11659-11671, 2011. PMC3064218

Complete List of Published Work in My Bibliography: http://www.ncbi.nlm.nih.gov/sites/myncbi/randall.mynatt.1/bibliography/40449404/public/?sort=date&direction=ascending

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