Randall Mynatt, Ph.D.
Ph.D., University of Tennessee, Knoxville, TN, 1991, Nutrition Sciences
Dr. Mynatt is Director of the Transgenic Core. His research laboratory utilizes an integrative approach combining genetic engineering techniques in mice, clinical studies, cellular physiology, and nutrition studies to understand the basis of obesity and type 2 diabetes.
It is well established that type 2 diabetes (T2D) is a progressive disease, and the hallmark of prediabetes is insulin resistance, which is strongly associated with obesity and the ectopic accumulation of lipids in skeletal muscle and liver. The use of dietary supplements, such as L-carnitine, that ameliorate lipid accumulation in skeletal muscle and liver represents a very attractive approach for adjunctive therapy of diabetes. 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.
L-carnitine is a conditionally essential nutrient that is synthesized endogenously or obtained from dietary sources. There are at least two major functions of L-carnitine. Fatty acids require L-carnitine for transport across the inner membrane of the mitochondria for ß-oxidation. Another important function of L-carnitine is to transport acetyl-CoA and possibly partially oxidized fatty acids from the mitochondria. The carnitine hypothesis posits that carnitine would reduce lipid metabolites within skeletal muscle via increased oxidation and increased mitochondrial export and that this reduction in lipotoxic metabolites would lead to an increase in insulin signaling and improve mitochondrial capacity.
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. These data suggest that abnormalities in fuel metabolism may arise from the mitochondrial accumulation of lipotoxic metabolites. Additionally, carnitine insufficiency is suspected as causative to mitochondrial dysfunction and insulin resistance. Low carnitine levels in severely obese rats were associated with aberrant mitochondrial fuel metabolism, whereas oral carnitine supplementation reversed these perturbations in concert with improved glucose tolerance and increased acylcarnitine efflux. These results provide the initial “proof of concept” that dietary carnitine is effective at improving insulin-stimulated glucose utilization and in reversing the abnormalities of fuel metabolism associated with T2D.
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.
Research in this laboratory is supported by grants from the American Diabetes Association and the National Institutes of Health.
Wicks, S, Vandanmagsar, B, Haynie, KR, Zhang, J, Noland, RC, Mynatt, RL. Impaired mitochondrial fat oxidation induces adaptive remodeling of muscle metabolism. Cell Metabolism (In revision)
Haynie, KR, Vandanmagsar, B, Wicks, S, Zhang, J, Mynatt, RL. Inhibition of Carnitine Palymitoyltransferase1b Induces Cardiac Hypertrophy and Mortality in Mice. Diabetes, Obesity and Metabolism (under final review)
Ganesh Kumar K, Zhang J, Gao S, Rossi J, McGuinness OP, Halem HH, Culler MD, Mynatt RL and Butler AA. Adropin-Deficiency is Associated With Increased Adiopsity and Insulin Resistance. Obesity, 2012 (Epub ahead of print)
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.
Kruger C, Kumar KG, Mynatt RL, Volaufova J, Richards BK. Brain Transcriptional Responses to High-Fat Diet in Acads-Deficient Mice Reveal Energy Sensing Pathways. PLoS ONE 7(8): e41709, 2012.
Vandanmagsar B, Youm Y-H, Ravussin A, Galgani J, Stadler K, Mynatt RL, Ravussinn E, Stephens JM, and Dixit VD. The NLRP3 Inflammasome Instigates Obesity-Induced inflammation and Insulin Resistance. Nature Medicine 17:179-188, 2011.
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.
Kashfi K, Mynatt RL, Park EA, Cook GA. Membrane microenvironment regulation of carnitine palmitoyltranferases I and II. Biochem Soc Trans 39:833-837, 2011.
Begriche K, Levasseur PR, Zhang J, Rossi J, Skorupa D, Sold LA, Young B, Burris TP, Marks DL, Mynatt RL and Butler AA. 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, 2011. PMC3220494.
Tang T, Zhang J, Yin J, Staszkiewicz J, Gawronska-Kozak B, Jung DY, Ko HJ, Ong H, Kim JK, Mynatt RL, Martin RJ, Keenan M, Gao Z, and Ye J. Uncoupling of Inflammation and Insulin Resistance by NF-kappaB in Transgenic Mice through Elevated Energy Expenditure. Journal of Biological Chemistry 285:4637-4644, 2010. PMC2836069
Yang H, Youm YH, Vandanmagsar B, Ravussin A, Gimble JM, Greenway F, Stephens JM, Mynatt RL and Dixit VD. Obesity increases the production of pro-inflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: Implications for systemic inflammation and insulin-resistance. The Journal of Immunology 185:1836-1845, 2010.
Mynatt RL Carnitine and Type 2 Diabetes. Diabetes Metabolism Research and Reviews 25 Suppl 1:S45-9, 2009.
White UA, Stewart WC, Mynatt RL, and Stephens JM. Neuropoietin attenuates adipogenesis and induces insulin resistance in adipocytes. Journal of Biological Chemistry 283:22505-22512, 2008. PMC2504895
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. Identification of Adropin as a secreted factor linking dietary macronutrient intake with energy homeostasis and lipid metabolism. Cell Metabolism 8:468-481, 2008. PMC2746325.
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.
Wu X, Zvonic S, Floyd ZE, Kilroy G, Goh BC, Hernandez TL, Eckel RH, Mynatt RL, and Gimble JM. Induction of Circadian Gene Expression in Human Subcutaneous Adipose-derived Stem Cells. Obesity 15:2560-2570, 2007.