Optimizing Nutritional Strategies to Promote Growth in Newborns Teresa A. Davis, Ph.D. Professor of Pediatrics USDA/ARS Children s Nutrition Research Center, Baylor College of Medicine, Houston, TX
Disclosure Statement Affiliation/Financial Interest Editor-in-Chief Board of Directors Research Funding Organization The Journal of Nutrition American Society of Animal Science NIH 5R01HD072891 NIH 9R01HD085573 USDA NIFA 2013-67015-20438 USDA CRIS 6250-51000-055 Abbott Nutrition
LOW BIRTH WEIGHT INFANTS 10% Births in U.S. and 15-20% worldwide LBW = <2500 g or <5.5 pounds Most are born preterm = <37 weeks gestation Preterm birth is leading cause of child death Optimizing the nutritional management of LBW infants is crucial for their immediate and long-term health
LOW BIRTH WEIGHT INFANTS Most are extrauterine growth restricted and small at hospital discharge Adverse long-term developmental outcomes are incurred Cognitive deficit Motor impairment Altered body composition high fat to lean body mass ratio Obesity, insulin resistance, Type 2 diabetes Metabolic syndrome, cardiovascular disease
LOW BIRTH WEIGHT INFANTS Extrauterine growth restriction of LBW infants is frequently due to our inability to provide adequate nutrition Initially fed total parenteral nutrition (TPN) due to intolerance to oral feeds Advanced gradually from TPN to enteral feeding
Orogastric Tube Feeding Bolus Continuous Pulsatile pattern of hormones and substrates Low, constant level of hormones and substrates? Which feeding pattern is more beneficial for promoting lean growth in infants is unknown
Neonatal Piglet Model To identify new strategies to optimize the nutritional management and improve the growth of low birth weight infants Ethical considerations limit human infant studies Anatomy and metabolism similar to infants Body size enables many experimental approaches o o o repeated sampling tracer kinetics feeding modality
Feeding Stimulates Muscle Protein Synthesis by Eliciting a Rise in Circulating Insulin and Amino Acids that Activate Insulin and Amino Acid Signaling Pathways Food Insulin Amino Acids Muscle Protein Synthesis
Insulin and Amino Acid Signaling Pathways that Regulate Protein Synthesis Insulin Insulin Receptor Food Amino Acids AA Leu Gln Gln Na + PI3-K PDK IRS-1 PTP1B Leu LAT-1 Gln Gln Na + SNAT-2 AA PAT-1 PTEN Ragulator Rag A-D Rheb FKBP38 PKB AMPK TSC2 TSC1 mtorc1 Raptor mtor GβL PRAS40 AA PAT-1 eif2 S6K1 eif4e 4EBP1 eef2 kinase Newly synthesized protein eif2b Met-tRNA eif4e eif4g rps6 mrna 60S AAAAA 40S eef2 Initiation Elongation Termination Protein Synthesis
Question Is bolus feeding more beneficial than continuous feeding because it activates the signaling components that regulate protein synthesis?
Neonatal pigs Gastric tube for 24 h Formula (240 ml kg -1 BW d -1 ) Methods Continuous 10 ml kg -1 BW h -1 Bolus 40 ml kg -1 BW q4h 0 4 8 12 16 20 24 Hours
µu ml -1 AU %/d 80 60 40 20 0 Insulin Bolus Intermittent Continuous tinuous Meal 0 4 8 12 16 20 24 Hours nmol ml -1 Amino Acids 1200 1000 800 600 400 200 0 0 4 8 12 16 20 24 Hours 2.0 1.5 1.0 0.5 0 Translation initiation Continuous * 35 30 * 25 20 15 10 5 0 Bolus Protein synthesis Continuous Bolus Gazzaneo et al, J Nutr, 141: 2152, 2011.
. Body weight, kg Lean mass, kg Bolus Feeding Compared to Continuous Feeding Increases Lean Growth Body weight Lean gain 6 5 4 3 * * * * * Bolus Continuous 3 2 1 * 2 0 0 3 6 9 12 15 18 21 Days 0 Continuous Bolus
Conclusion: Orogastric Tube Feeding Bolus Continuous Pulsatile pattern of amino acids & insulin Activates amino acid & insulin signaling pathways Stimulates protein synthesis Increases lean growth Low, constant level of amino acids & insulin Mutes amino acid & insulin signaling pathways Blunts protein synthesis Restricts lean growth
Perspectives Intermittent bolus feeding is the preferable feeding method to enhance lean growth during gastric tube feeding.
Some low birth weight infants must be fed continuously because of meal feeding intolerance. Can strategies be developed to improve the growth of infants who must be continuously fed?
Essential amino acid Leucine Signaling molecule that stimulates intracellular signaling pathways that regulate protein synthesis Primary driver of the increase in protein synthesis in skeletal muscle after a meal
Protein synthesis (%/day) eif4g eif4e (AU) Leucine Is a Primary Driver of the Rapid Increase in Protein Synthesis after a Meal 20 Protein Synthesis * 24 Translation Initiation Escobar et al, J Nutr 140:1418, 2010. 15 18 * 10 12 5 6 0 Control Leu Ile Val 0 Control Leu Ile Val
Can pulsatile delivery of a leucine supplement during continuous feeding enhance lean growth by mimicing the pulse of leucine that occurs after a meal?
Neonatal pigs, 2.3 ± 0.1 kg CONT + alanine CONT + leucine Methods Continuous infusion of formula by orogastric tube for 21 d (10 ml kg -1 BW h -1 ) Parenterally pulsed with leucine (800 μmol kg -1 BW h -1 ) or alanine (isonitrogenous control) at 4 h intervals
Body weight (kg) Lean gain (kg) Fat gain (kg) Pulses of leucine during continuous feeding for 21 days increased lean growth 4.0 Body Weight Leucine pulse * Control Lean Gain 1.6 * 0.2 Fat gain 3.0 1.2 0.8 0.1 * 2.0 0.0 0 3 6 9 12 15 18 21 Continuous Feeding in Days 0.4 0.0 Control Leucine Pulse 0.0 Control Leucine Pulse Boutry et al, Am J Physiol, 310: E699, 2016.
Weight (g) Weight (g) Weight (g) Leucine pulses increased muscle weight LD Gastrocnemius Soleus 60 a a 4 40 b b 3 b a 2 20 1 0 Control Leucine Control Leucine 0 Control Leucine Boutry et al, Am J Physiol, 310: E699, 2016.
Protein Synthesis (%.d -1 ) Protein Synthesis (%.d -1 ) Protein Synthesis (%.d -1 ) Leucine pulses increased muscle protein synthesis LD Gastrocnemius Soleus 10 8 6 4 b a 8 a 6 b 4 10 8 6 4 b a 2 2 2 0 Control Leucine 0 Control Leucine 0 Control Leucine Boutry et al, Am J Physiol, 310: E699, 2016.
S6K1 Phosphorylation (AU) 4EBP1 Phosphorylation (AU) eif4g eif4e Complex (AU) Leucine pulses increased the activation of translation initiation factors 1.2 0.8 b a 2.0 1.5 1.0 b a 1.5 1.0 a 0.4 0.5 0.5 b 0.0 Control Leucine 0.0 Control Leucine 0.0 Control Leucine Boutry et al, Am J Physiol, 310: E699, 2016.
Conclusions Pulsatile delivery of a leucine supplement during continuous enteral feeding in neonates activates the translation initiation pathway that increases protein synthesis in skeletal muscle. This stimulatory effect of leucine supplementation on muscle protein synthesis leads to an increase in lean growth.
Can supplementation with leucine metabolites enhance protein synthesis in the neonate?
Leucine Urine (10-40%) Branched Chain Amino Acid Transferase β-hydroxyβ-methylbutyrate (HMB) CO2 HMB-CoA KIC-dioxygenase (cytosol) α-ketoglutarate Glutamate α-ketoisocaproate (KIC) O2 CO2 MC-CoA CO2 Enol-CoA hydrase (when biotin is deficient) Alanine Pyruvate Branched Chain α-ketoacid Dehydrogenase (mitochondria) H2O CO2 Glutamine Isovaleryl-CoA Isovaleryl-CoA dehydrogenase β-methyl-crotonyl-coa (MC-CoA) CO2 Biotin MC-CoA carboxylase β-methyl-gluconyl-coa (MG-CoA) HMG-CoA reductase Mevalonate HMG-CoA HMG-CoA synthase MG-CoA β-hydroxy-β-methylglutaryl-coa (HMG-CoA) Cholesterol Acetoacetyl-CoA Acetyl-CoA MG-CoA lyase (liver) Acetoacetate Nissen et al, J Nutr 130:1937, 2000.
Question Can supplementation with the leucine metabolite, β- hydroxy-β-methylbutyrate (HMB), stimulate protein synthesis in neonates? HMB may promote lean gain and strength in adults.
Methods Treatment groups (n = 7-9/treatment; 5-7 d-old): 1) Fasted (F) 2) Low Protein Diet (LP) 3) Low Protein Diet + HMB 4 µmol/kg/day (HMB-4) 4) Low Protein Diet + HMB 40 µmol/kg/day (HMB-40) 5) Low Protein Diet + HMB 80 µmol/kg/day (HMB-80) 6) High Protein Diet (HP) Gastric tube feeding every 4 hours for 24 hours
HMB Increases the Activation of Regulators of Translation Initiation in Skeletal Muscle Association of eif4e with eif4g Kao et al, Am J Physiol, 310:E1072, 2016.
Enteral HMB Supplementation Increases Muscle Protein Synthesis Kao et al, Am J Physiol, 310:E1072, 2016.
Perinatal Muscle Growth Neonate myofibril Adult mature myofiber satellite cell division myonuclear accretion protein accretion Hypertrophy protein synthesis
HMB Supplementation Stimulates Satellite Cell Proliferation in Muscle Kao et al, Am J Physiol, 310:E1072, 2016.
CONCLUSIONS Enteral HMB supplementation in neonatal piglets: Increases skeletal muscle protein synthesis by enhancing the activation of translation initiation via the mtor pathway Increases satellite cell proliferation
Perspectives Supplementation with leucine or its metabolite, HMB may be useful adjuncts to the nutritional management of LBW infants to promote their growth.
Thank you!