Role of Leucine Metabolism in Leucine Signaling

Summary

Principal Investigator: CHRISTOPHER JOHN LYNCH
Abstract: DESCRIPTION (provided by applicant): The long-term goal of these studies is to determine the role of branched chain amino acid (BCAA) metabolism in obesity and nutrient signaling from leucine. Results from a number of studies indicate that increasing dietary protein in the diet has a beneficial effect on insulin sensitivity, satiety, lean body mass and resistance to obesity. Branched chain amino acids (BCAAs) or leucine appear to be the active dietary component. Paradoxically, BCAAs are elevated in obesity and their some of their targets, such PKC-? and the mTOR cell signaling pathway, appear to promote Ser-phosphorylation of IRS-1, a cause of insulin resistance. Further, substrates of mTOR, lipin, S6K1 and 4EBP1&2, have been alternatively implicated in either obesity or resistance to obesity. Since some studies suggest that raising BCAAs in the diet would be beneficial for obesity whereas other findings predict a worsening of obesity co-morbidities;it is not entirely clear what might be expected from raising BCAAs in the diet or preventing peripheral BCAA metabolism. The proposed research will address that and the following questions. What is the role of BCAA metabolism in nutrient signaling leading to the activation of PKC-? and the mTOR pathway? Does defective metabolism play a role in the elevations of BCAAs observed in obesity and can this be reversed by weight loss intervention? In the last funding period, we generated a line of transgenic mice (BCATm KO) deficient in the first step in BCAA metabolism catalyzed by the mitochondrial branched chain aminotransferase isozyme (BCATm) found in most peripheral (non-neuronal) tissues. The block in BCAA metabolism will be exploited to help clarify these inconsistencies and questions related to leucine signaling and metabolism. The BCATm KO has persistently elevated BCAAs, but these can be adjusted over a wide range by dietary manipulation. It also has an obesity- related metabolic phenotype: decreased adipose tissue mass and fat cell size, markedly improved insulin sensitivity and glucose tolerance, increased feeding-related energy expenditure and robust resistance to diet- induced obesity. Remarkably, these changes occur in the context of increased food consumption. The mechanisms underlying the improved insulin sensitivity are not understood and will be investigated here. The resistance to diet-induced obesity and increased energy expenditure found in the BCAT2 KO appear to be due to novel futile cycle that we will elucidate. The specific aims to address these questions are to: 1) Elucidate the mechanisms involved in the increased energy expenditure observed in the BCAT2 KO mouse. 2) Test the alternate hypotheses that the insulin sensitivity and resistance to diet-induced obesity of the BCAT2 KO is due to either elevated BCAAs or the loss of mitochondrial BCAA metabolism. 3) To determine whether leucine metabolism is needed for mTOR and PKC-5 activation in heart and skeletal muscle. 4) Determine the mechanism through which plasma BCAAs are elevated in obesity. PUBLIC HEALTH RELEVANCE: We are examining the role of branched chain amino acid (BCAA) metabolism in nutrient signaling and obesity. BCAAs are believed by some to be the active portion of recently emerging high protein diets (Akins, South Beach), "protein water" as well as BCAA- and Whey-supplemented snack bars for body weight control. The implication of our ongoing research is that blocking the first step in BCAA metabolism with a drug, or to a less extent increasing dietary BCAAs, will promote weight loss.
Funding Period: ----------------2003 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. pmc Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents
    Vance L Albaugh
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
    Obesity (Silver Spring) 14:36-51. 2006
  2. pmc Quantification of branched-chain keto acids in tissue by ultra fast liquid chromatography-mass spectrometry
    Kristine C Olson
    Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
    Anal Biochem 439:116-22. 2013
  3. pmc Leucine and protein metabolism in obese Zucker rats
    Pengxiang She
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
    PLoS ONE 8:e59443. 2013
  4. pmc Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival
    Theresa D Carr
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
    Cancer Prev Res (Phila) 5:1394-404. 2012
  5. pmc Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism
    Pengxiang She
    Dept of Cellular and Molecular Physiology, MC H166, Penn State Univ College of Medicine, 500 University Dr, Hershey, PA 17033, USA
    Am J Physiol Endocrinol Metab 293:E1552-63. 2007
  6. pmc Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle
    Pengxiang She
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Cell Metab 6:181-94. 2007
  7. ncbi Nutrient signaling components controlling protein synthesis in striated muscle
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 137:1835-43. 2007
  8. ncbi Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Am J Physiol Endocrinol Metab 290:E631-42. 2006
  9. ncbi Leucine in food mediates some of the postprandial rise in plasma leptin concentrations
    Christopher J Lynch
    Dept of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Am J Physiol Endocrinol Metab 291:E621-30. 2006
  10. ncbi Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 136:2284-90. 2006

Scientific Experts

  • Charles Lang
  • Pengxiang She
  • CHRISTOPHER JOHN LYNCH
  • Andras Hajnal
  • Thomas C Vary
  • Derek M Culnan
  • Vance L Albaugh
  • Robert N Cooney
  • Kristine C Olson
  • Theresa D Carr
  • V L Albaugh
  • Jia Li
  • Mark A Herman
  • Rachel L Fogle
  • Ali Nairizi
  • Peng Li
  • Gang Lu
  • Katia Meirelles
  • Gina Deiter
  • Leonard S Jefferson
  • Gang Chen
  • Tedd D Elich
  • Olga Ilkayeva
  • STEVEN BREAZEALE
  • John DiGiovanni
  • Lisa M Shantz
  • Kevin P Maresca
  • Brett R Wenner
  • John L Joyal
  • J L Joyal
  • K P Maresca
  • J G Judson
  • Zhijie Chang
  • Bruce A Stanley
  • Huayan Wang
  • Yuan Li
  • Barbara B Kahn
  • Odile D Peroni
  • Xinbao Hao
  • Mary Palopoli
  • Kathryn F LaNoue
  • Yinyuan Wu
  • Xianlin Han
  • Jingwei Xiong
  • Yuguang Shi
  • Xiaolei Liu
  • Caroline Romestaing
  • Vance Albaugh
  • Mingjie Sun
  • Chao Sun
  • Bruce Stanley
  • Tamer Ahmed
  • Sarah Warburton
  • Haipeng Sun
  • Susan M Hutson
  • Thomas M Vondriska
  • Peipei Ping
  • Ji Youn Youn
  • Darrell A Knabe
  • Sung Woo Kim
  • Guoyao Wu
  • Yibin Wang
  • Hua Cai
  • Joshua C Anthony
  • Scot R Kimball
  • Beth Halle
  • Susan L Lynch
  • Nicholas T Bello
  • Cathy R Henry

Detail Information

Publications29

  1. pmc Hormonal and metabolic effects of olanzapine and clozapine related to body weight in rodents
    Vance L Albaugh
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
    Obesity (Silver Spring) 14:36-51. 2006
    ..To characterize a model of atypical antipsychotic drug-induced obesity and evaluate its mechanism...
  2. pmc Quantification of branched-chain keto acids in tissue by ultra fast liquid chromatography-mass spectrometry
    Kristine C Olson
    Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
    Anal Biochem 439:116-22. 2013
    ..8-32,000 nM). Liquid chromatography-mass spectrometry run times for this assay were less than 5 min, facilitating high throughput, and the OPD derivatives were found to be stable over several days...
  3. pmc Leucine and protein metabolism in obese Zucker rats
    Pengxiang She
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, United States of America
    PLoS ONE 8:e59443. 2013
    ..Elevated BCAAs/BCKAs may contribute to observed elevations in protein synthesis and BCAA oxidation...
  4. pmc Inhibition of mTOR suppresses UVB-induced keratinocyte proliferation and survival
    Theresa D Carr
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, 500 University Drive, Hershey, PA 17033, USA
    Cancer Prev Res (Phila) 5:1394-404. 2012
    ..Our findings underscore the importance of both mTOR complexes in mediating UVB-induced signaling in keratinocytes and provide new insight into the pathogenesis of skin cancer...
  5. pmc Obesity-related elevations in plasma leucine are associated with alterations in enzymes involved in branched-chain amino acid metabolism
    Pengxiang She
    Dept of Cellular and Molecular Physiology, MC H166, Penn State Univ College of Medicine, 500 University Dr, Hershey, PA 17033, USA
    Am J Physiol Endocrinol Metab 293:E1552-63. 2007
    ..Our results are consistent with the idea that tissue-specific alterations in BCAA metabolism, in liver and adipose tissue but not in muscle, may contribute to the rise in plasma BCAAs in obesity...
  6. pmc Disruption of BCATm in mice leads to increased energy expenditure associated with the activation of a futile protein turnover cycle
    Pengxiang She
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Cell Metab 6:181-94. 2007
    ..These observations suggest that elevated BCAAs and/or loss of BCAA catabolism in peripheral tissues play an important role in regulating insulin sensitivity and energy expenditure...
  7. ncbi Nutrient signaling components controlling protein synthesis in striated muscle
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 137:1835-43. 2007
    ....
  8. ncbi Meal feeding enhances formation of eIF4F in skeletal muscle: role of increased eIF4E availability and eIF4G phosphorylation
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Am J Physiol Endocrinol Metab 290:E631-42. 2006
    ..eIF4E complex assembly through increased phosphorylation of eIF4G and decreased association of 4E-BP1 with eIF4E...
  9. ncbi Leucine in food mediates some of the postprandial rise in plasma leptin concentrations
    Christopher J Lynch
    Dept of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Am J Physiol Endocrinol Metab 291:E621-30. 2006
    ..Thus Leu appears to regulate most of the effects of dietary amino acids on the postprandial rise in plasma leptin but is responsible only for part of the leptin response to meal feeding...
  10. ncbi Meal feeding stimulates phosphorylation of multiple effector proteins regulating protein synthetic processes in rat hearts
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Penn State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 136:2284-90. 2006
    ....
  11. ncbi Rapamycin limits formation of active eukaryotic initiation factor 4F complex following meal feeding in rat hearts
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 137:1857-62. 2007
    ..Furthermore, the rapamycin-sensitive reductions in phosphorylation of eIF4G may also lead to decreased formation of active eIF4G-eIF4E complex...
  12. ncbi Rapamycin blunts nutrient stimulation of eIF4G, but not PKCepsilon phosphorylation, in skeletal muscle
    Thomas C Vary
    Department of Cellular and Molecular Physiology, Rm C4710, Penn State University College of Medicine, H166, 500 University Drive, Hershey, PA 17033, USA
    Am J Physiol Endocrinol Metab 293:E188-96. 2007
    ..The latter observation implies that the effects observed with rapamycin were the result of modulation of skeletal muscle signaling mechanisms responsible for eIF4G phosphorylation...
  13. pmc Impact of chronic alcohol ingestion on cardiac muscle protein expression
    Rachel L Fogle
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, USA
    Alcohol Clin Exp Res 34:1226-34. 2010
    ..However, the full extent to which myocardial proteins are affected by chronic alcohol consumption remains unresolved...
  14. pmc Apolipoprotein A-IV, a putative satiety/antiatherogenic factor, rises after gastric bypass
    Derek M Culnan
    1Department of Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
    Obesity (Silver Spring) 17:46-52. 2009
    ..In addition, the findings provide evidence validating the use of iTRAQ proteomics in discovery-based studies of post-RYGBP improvements in obesity-related medical comorbidities...
  15. pmc Molecular characterization of skeletal muscle atrophy in the R6/2 mouse model of Huntington's disease
    Pengxiang She
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    Am J Physiol Endocrinol Metab 301:E49-61. 2011
    ....
  16. pmc Cardiolipin remodeling by ALCAT1 links oxidative stress and mitochondrial dysfunction to obesity
    Jia Li
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Cell Metab 12:154-65. 2010
    ..Collectively, these findings identify a key role of ALCAT1 in regulating CL remodeling, mitochondrial dysfunction, and susceptibility to DIO...
  17. pmc Ileal interposition improves glucose tolerance and insulin sensitivity in the obese Zucker rat
    Derek M Culnan
    Departments of Surgery, Pennsylvania State University College of Medicine, Hershey, USA
    Am J Physiol Gastrointest Liver Physiol 299:G751-60. 2010
    ..These findings support the concept that anatomic and endocrine alterations in gut function play a role in the improvements in glucose homeostasis after the IT procedure...
  18. pmc Gastric bypass surgery alters behavioral and neural taste functions for sweet taste in obese rats
    Andras Hajnal
    Dept of Neural and Behavioral Sciences, The Milton S Hershey Medical Center, The Pennsylvania State Univ, Hershey, PA 17033, USA
    Am J Physiol Gastrointest Liver Physiol 299:G967-79. 2010
    ..An understanding of the underlying mechanisms for reduced preferences for sweet taste could help in developing less invasive treatments for obesity...
  19. pmc BCATm deficiency ameliorates endotoxin-induced decrease in muscle protein synthesis and improves survival in septic mice
    Charles H Lang
    Department of Cellular and Molecular Physiology, and Surgery, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
    Am J Physiol Regul Integr Comp Physiol 299:R935-44. 2010
    ....
  20. pmc Atypical antipsychotics rapidly and inappropriately switch peripheral fuel utilization to lipids, impairing metabolic flexibility in rodents
    Vance L Albaugh
    Department of Cellular and Molecular Physiology, Penn State College of Medicine, Hershey, PA 17033, USA
    Schizophr Bull 38:153-66. 2012
    ....
  21. pmc Mechanisms of glucose homeostasis after Roux-en-Y gastric bypass surgery in the obese, insulin-resistant Zucker rat
    Katia Meirelles
    Departments of Surgery, Pennsylvania State University College of Medicine, Hershey, 17033, USA
    Ann Surg 249:277-85. 2009
    ..The current study examines changes in food intake, weight loss, body fat depots, oxygen consumption, insulin sensitivity, and incretin levels as potential mechanisms for improved glucose tolerance after Roux-en-Y gastric bypass (RYGB)...
  22. pmc Skeletal muscle protein balance in mTOR heterozygous mice in response to inflammation and leucine
    Charles H Lang
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Am J Physiol Endocrinol Metab 298:E1283-94. 2010
    ..These data support the idea that the LPS-induced reduction in mTOR activity is relatively more important in regulating skeletal muscle mass in response to nutrient stimulation than under basal conditions...
  23. pmc Olanzapine promotes fat accumulation in male rats by decreasing physical activity, repartitioning energy and increasing adipose tissue lipogenesis while impairing lipolysis
    V L Albaugh
    Department of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    Mol Psychiatry 16:569-81. 2011
    ..Collectively, these results suggest that olanzapine exerts several metabolic effects that together favor increased accumulation of fuel into adipose tissue, thereby increasing adiposity...
  24. pmc Alcohol-induced IGF-I resistance is ameliorated in mice deficient for mitochondrial branched-chain aminotransferase
    Charles H Lang
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 140:932-8. 2010
    ..These data suggest that whereas the sustained elevation in plasma BCAA is not sufficient to ameliorate the catabolic effect of acute alcohol intoxication on muscle protein synthesis, it does improve the anabolic effect of IGF-I...
  25. pmc Disruption of BCAA metabolism in mice impairs exercise metabolism and endurance
    Pengxiang She
    Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA
    J Appl Physiol (1985) 108:941-9. 2010
    ..Thus BCAA metabolism may regulate exercise capacity in mice...
  26. pmc Adipose tissue branched chain amino acid (BCAA) metabolism modulates circulating BCAA levels
    Mark A Herman
    Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA
    J Biol Chem 285:11348-56. 2010
    ..These results demonstrate for the first time the capacity of adipose tissue to catabolize circulating BCAAs in vivo and that coordinate regulation of adipose-tissue BCAA enzymes may modulate circulating BCAA levels...
  27. pmc Lactating porcine mammary tissue catabolizes branched-chain amino acids for glutamine and aspartate synthesis
    Peng Li
    Department of Animal Science and Faculty of Nutrition, Texas A and M University, College Station, TX 77843, USA
    J Nutr 139:1502-9. 2009
    ....
  28. pmc Protein phosphatase 2Cm is a critical regulator of branched-chain amino acid catabolism in mice and cultured cells
    Gang Lu
    Division of Molecular Medicine, Department of Anesthesiology, David Geffen School of Medicine, UCLA, Los Angeles, California 90095, USA
    J Clin Invest 119:1678-87. 2009
    ..These results indicate that PP2Cm is the endogenous BCKD phosphatase required for nutrient-mediated regulation of BCKD activity and suggest that defects in PP2Cm may be responsible for a subset of human MSUD...
  29. pmc Leucine supplementation of drinking water does not alter susceptibility to diet-induced obesity in mice
    Ali Nairizi
    Penn State Hershey Institute for Diabetes and Obesity and Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine, Hershey, PA 17033, USA
    J Nutr 139:715-9. 2009
    ..Taken together, the results do not provide evidence that either Leu or BCAA supplementation of drinking water ameliorates diet-induced obesity in mice, although it may improve glycemia...