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AHS 2013 Bibliography – “What Is Metabolic Flexibility, and Why Is It Important?” – J. Stanton

Thanks to everyone who attended my presentation at the 2013 Ancestral Health Symposium, “What Is Metabolic Flexibility, and Why Is It Important?” Since the videos are unwatchable due to technical and production failures, I’ve posted the full text and slides here. (And if you haven’t seen it already, I recommend watching the video, and reading the bibliography, of my 2012 AHS presentation.)

Meanwhile, here are the references for the facts I discussed, and the data sources for the graphs and quotes in my slides. I’ve organized them by section.

Introduction, “What Is Metabolic Flexibility?”, “How Is Metabolic Flexibility Measured?”, “Why Is Metabolic Flexibility Important?”

Explanations of all the basics—including the biochemistry of cellular respiration, the RER/RQ, its measurement, and its limitations—can be found in any respectable exercise physiology textbook. I have read and recommend this one:

W. Larry Kenney, Jack Wilmore, David Costill
Physiology of Sport and Exercise, 5th Edition
2011, Human Kinetics Publishing, ISBN 978-0736094092

“…Met flex lets us burn more stored fat and produce more energy at all levels of effort.”

Diabetes Metab. 2001 Sep;27(4 Pt 1):466-74.
Balance of substrate oxidation during submaximal exercise in lean and obese people.
Pérez-Martin A, Dumortier M, Raynaud E, Brun JF, Fédou C, Bringer J, Mercier J.

“What Happens When Metabolic Flexibility Is Impaired?”, and “What Are The Real-World Consequences Of Impaired Metabolic Flexibility?”

Am J Physiol Endocrinol Metab. 2008 November; 295(5): E1009–E1017.
Metabolic flexibility and insulin resistance
Jose E. Galgani, Cedric Moro, and Eric Ravussin
(Fulltext here)

Diabetes. 2007 Aug;56(8):2046-53. Epub 2007 Apr 24.
Impaired fat oxidation after a single high-fat meal in insulin-sensitive nondiabetic individuals with a family history of type 2 diabetes.
Heilbronn LK, Gregersen S, Shirkhedkar D, Hu D, Campbell LV.
(Fulltext here)

J Clin Endocrinol Metab. 2006 Apr;91(4):1462-9. Epub 2006 Jan 31.
Fat oxidation before and after a high fat load in the obese insulin-resistant state.
Blaak EE, Hul G, Verdich C, Stich V, Martinez A, Petersen M, Feskens EF, Patel K, Oppert JM, Barbe P, Toubro S, Anderson I, Polak J, Astrup A, Macdonald IA, Langin D, Holst C, Sørensen TI, Saris WH.
(Fulltext here)

Am J Clin Nutr. 1983 Nov;38(5):680-93.
Energy expenditure and postprandial thermogenesis in obese women before and after weight loss.
Bessard T, Schutz Y, Jéquier E.

Am J Clin Nutr. 1984 Sep;40(3):542-52.
Diet-induced thermogenesis measured over a whole day in obese and nonobese women.
Schutz Y, Bessard T, Jéquier E.

Am J Physiol. 1998 Jan;274(1 Pt 1):E155-61.
Fat metabolism in formerly obese women.
Ranneries C, Bülow J, Buemann B, Christensen NJ, Madsen J, Astrup A.
(Fulltext here)

“Why Is Metabolic Flexibility Impaired?”

Diabetes. 2007 Mar;56(3):720-7.
Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle.
Ukropcova B, Sereda O, de Jonge L, Bogacka I, Nguyen T, Xie H, Bray GA, Smith SR.
(Fulltext here)

PLoS One. 2013;8(2):e51648. doi: 10.1371/journal.pone.0051648. Epub 2013 Feb 13.
Relationships between mitochondrial function and metabolic flexibility in type 2 diabetes mellitus.
van de Weijer T, Sparks LM, Phielix E, Meex RC, van Herpen NA, Hesselink MK, Schrauwen P, Schrauwen-Hinderling VB.
(Fulltext here)
     “Upon a more thorough analysis of the different components of metabolic flexibility, we found that in vivo mitochondrial function was the single predictor of basal RER. In contrast, insulin-stimulated RER was mainly determined by glucose disposal rate and not by in vivo mitochondrial function.”

Am J Physiol Endocrinol Metab. 2010 Jul;299(1):E14-22. doi: 10.1152/ajpendo.00187.2010. Epub 2010 May 4.
Oxidation of intramyocellular lipids is dependent on mitochondrial function and the availability of extracellular fatty acids.
Corpeleijn E, Hessvik NP, Bakke SS, Levin K, Blaak EE, Thoresen GH, Gaster M, Rustan AC.
(Fulltext here)

“How Does Metabolic Flexibility Become Impaired?”

AJP – Endo November 1990 vol. 259 no. 5 E650-E657
Low ratio of fat to carbohydrate oxidation as predictor of weight gain: study of 24-h RQ
F. Zurlo, S. Lillioja, A. Esposito-Del Puente, B. L. Nyomba, I. Raz, M. F. Saad, B. A. Swinburn, W. C. Knowler, C. Bogardus, and E. Ravussin

Corpeleijn 2010

PLoS ONE 8(8): e70435. doi:10.1371/journal.pone.0070435
Segregation of a Latent High Adiposity Phenotype in Families with a History of Type 2 Diabetes Mellitus Implicates Rare Obesity-Susceptibility Genetic Variants with Large Effects in Diabetes-Related Obesity
Arthur B. Jenkins, Marijka Batterham, Dorit Samocha-Bonet, Katherine Tonks, Jerry R. Greenfield, Lesley V. Campbell
(Fulltext available)

Heilbronn 2007: “…An impaired ability to increase fatty acid oxidation precedes the development of insulin resistance in genetically susceptible individuals.”

J Clin Endocrinol Metab. 2011 February; 96(2): 494–503.
Skeletal Muscle Mitochondria in Insulin Resistance: Differences in Intermyofibrillar Versus Subsarcolemmal Subpopulations and Relationship to Metabolic Flexibility
Peter Chomentowski, Paul M. Coen, Zofia Radiková, Bret H. Goodpaster, and Frederico G. S. Toledo
(Fulltext here)
     “…Mitochondrial content is lower across the continuum of insulin sensitivity and is not limited to T2DM.”

Ukropcova 2007: “Metabolic inflexibility, lower adaptation to a HFD, and reduced muscle mitochondrial mass cluster together in subjects with a family history of diabetes, supporting the role of an intrinsic metabolic defect of skeletal muscle in the pathogenesis of insulin resistance.”

How Can We Regain Our Metabolic Flexibility?

J Appl Physiol. 2009 Apr;106(4):1079-85. doi: 10.1152/japplphysiol.91262.2008. Epub 2009 Feb 5.
Effect of exercise intensity and volume on persistence of insulin sensitivity during training cessation.
Bajpeyi S, Tanner CJ, Slentz CA, Duscha BD, McCartney JS, Hickner RC, Kraus WE, Houmard JA.
(Fulltext here)

Am J Physiol Endocrinol Metab. 2008 Apr;294(4):E726-32. doi: 10.1152/ajpendo.00354.2007. Epub 2008 Feb 5.
Skeletal muscle lipid oxidation and obesity: influence of weight loss and exercise.
Berggren JR, Boyle KE, Chapman WH, Houmard JA.
(Fulltext here)
     “These data indicate that a defect in the ability to oxidize lipid in skeletal muscle is evident with obesity, which is corrected with exercise training but persists after weight loss.”

Am J Physiol Endocrinol Metab. 2012 Dec 15;303(12):E1440-5. doi: 10.1152/ajpendo.00355.2012. Epub 2012 Oct 9.
Effect of exercise training on metabolic flexibility in response to a high-fat diet in obese individuals.
Battaglia GM, Zheng D, Hickner RC, Houmard JA.
     “The increase in FAO with exercise training, however, enables the skeletal muscle of obese individuals to respond similarly to their lean counterparts when confronted with short-term excursion in dietary lipid.”

Diabetes. 2010 Mar;59(3):572-9. doi: 10.2337/db09-1322. Epub 2009 Dec 22.
Restoration of muscle mitochondrial function and metabolic flexibility in type 2 diabetes by exercise training is paralleled by increased myocellular fat storage and improved insulin sensitivity.
Meex RC, Schrauwen-Hinderling VB, Moonen-Kornips E, Schaart G, Mensink M, Phielix E, van de Weijer T, Sels JP, Schrauwen P, Hesselink MK.
(Fulltext here)

J Appl Physiol. 2008 Sep;105(3):825-31. doi: 10.1152/japplphysiol.90384.2008. Epub 2008 Jul 10.
Separate and combined effects of exercise training and weight loss on exercise efficiency and substrate oxidation.
Amati F, Dubé JJ, Shay C, Goodpaster BH.
(Free fulltext)

Diabetes. 2003 Sep;52(9):2191-7.
Enhanced fat oxidation through physical activity is associated with improvements in insulin sensitivity in obesity.
Goodpaster BH, Katsiaras A, Kelley DE.
(Free fulltext)

J Physiol. 2009 Oct 15;587(Pt 20):4949-61. doi: 10.1113/jphysiol.2009.175489. Epub 2009 Sep 1.
Improved insulin sensitivity after weight loss and exercise training is mediated by a reduction in plasma fatty acid mobilization, not enhanced oxidative capacity.
Schenk S, Harber MP, Shrivastava CR, Burant CF, Horowitz JF.
(Free fulltext)

Exercise increases mitochondrial size:

Am J Physiol Regul Integr Comp Physiol. 2007 Mar;292(3):R1271-8. Epub 2006 Nov 9.
Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity.
Tarnopolsky MA, Rennie CD, Robertshaw HA, Fedak-Tarnopolsky SN, Devries MC, Hamadeh MJ.
(Free fulltext)

J Clin Endocrinol Metab. 2006 Aug;91(8):3224-7. Epub 2006 May 9.
Changes induced by physical activity and weight loss in the morphology of intermyofibrillar mitochondria in obese men and women.
Toledo FG, Watkins S, Kelley DE.
(Free fulltext)

“Results May Vary”:

Am J Clin Nutr. 2000 Feb;71(2):450-7.
Fat and carbohydrate balances during adaptation to a high-fat diet.
Smith SR, de Jonge L, Zachwieja JJ, Roy H, Nguyen T, Rood JC, Windhauser MM, Bray GA.
(Free fulltext)


I thank Dr. William Lagakos, Mike T. Nelson, and Petro Dobromylskyj for contributing to my understanding.

Live in freedom, live in beauty.