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Obsit et mtabolismeprotique

3 octobre 2017

Pr. Yves BoirieService de Nutrition Clinique, CHU de Clermont-FerrandCentre de Recherche en Nutrition HumaineClermont-Ferrand

Human body composition phenotypes

Masse grasse ?Masse maigre ?

Obsit et Mtabolisme protique

Trop de gras ou trop peu de maigre ?

Masse maigre, moteur du renouvellement

protique : spcificits de lobsit

Applications cliniques potentielles

Obsit et Mtabolisme protique

Trop de gras ou trop peu de maigre ?

Masse maigre, moteur du renouvellement

protique : spcificits de lobsit

Applications cliniques potentielles

Large diversity of body phenotypes (CT scan)

IdenticalMuscle Mass(different FM)

IdenticalFat Mass(differentMuscle mass)

Martin L, J Clin Oncol 2013

BMI- and age-specific reference values for FFM and FFMI from 186,975 subjects

Franssen FME, JAMDA 2014

FFM/Bioelectrical impedance analysisFFMI=FFM/height

Body composition phenotypes

Char

ge

mt

abol

ique

Chap

acit

mc

aniq

ue

Vincent HK, Obes Rev 2009

Vincent HK, Obes Rev 2009

Obsit et Mtabolisme protique

Trop de gras ou trop peu de maigre ?

Masse maigre, moteur du renouvellement

protique : spcificits de lobsit

Applications cliniques potentielles

Synthesis (300 g/d)

Proteolysis (300 g/d)

Schematic overview of whole body proteinmetabolism in non-obese humans (70kg)

Intake (70 g/d)

Oxidation (70 g/d)

- Protein = 300g /10 kgTurnover = 3% protein/d- Cot E = 30-40% REE

Proteins(10 kg)

FFM 55kgfreeAA

(70 g)

Free AA

Proteins(10 kg)

Synthesis (350 g/d)

Intake (80-100 g/d)

Proteolysis (350 g/d)

Oxidation (80-100 g/d)

Protein turnover to be adjusted to changes in FFM in obese subjects

Proteins(12 kg)

Turnover = 350g /12 kg protein= 3% protein/d

Strong relationship between fat free mass and whole body protein turnover rate

R 2 = 0.679

R 2 = 0.697

40

60

80

100

120

140

160

30 40 50 60 70 80Fat-free mass (kg)

WB

Prot

ein

Turn

over

as L

eu fl

ux

(m

ol/m

in)

Older subjectsYoung subjects

Boirie Y, Int J Obes 2001

WB protein turnover normalized for FFM in steady conditions

?

Protein turnover rate may be affected by metabolic alterations associated with obesity

Impaired glucose metabolism

Insulin resistance

Low-grade inflammation

Higher FFA flux

Adipokines production

Impact on WB protein metabolism: response to anabolic factors like insulin or meal intake?

Chevalier S, Am J Clin Nutr 2005

Whole body proteinbreakdown is less

sensitive to the inhibitoryaction of insulin in obesity

Lower glucose uptake

Smaller inhibition of protein breakdown

Guillet C, JCEM 2009

Henderson GC, Obesity 2010

Lower protein turnover after caloric restriction but higher protein turnover in severely vs moderateobesity (despite adjustment to FFM): role of the adipose tissue in protein metabolism?

Whole body protein metabolismof the obese patient

WB protein turnover is higher in the obese but can be normalized after adjustment on lean body mass in stable conditions in moderately obesity

Fat mass may contribute to whole body proteinmetabolism in severely obese patients

The response of WB protein synthesis and breakdown to insulin and to meal intake isblunted ANABOLIC RESISTANCE ?

Muscle

Intestine

Liver

Kidney

Skin

~ 100 g/d

Tissue-specific protein metabolism

Free AA

(70 g)

Synthesis (300 g/d)

Intake

Proteolysis(300 g/d)

Oxidation

~ 140 g/d

Changes in tissue protein turnover?

Free AA

Intake

Ox

Protein 300g/d

NON-OBESE

Protein??

OBESE

Changes in tissue protein metabolism?

Free AA

Intake

Ox

Muscle

Intestine

Liver

Kidney

Adiposetissue

38%

5%

57%

NON-OBESE

Muscle

Intestine

Liver

KidneyAdiposetissue

23%

8%

69%

OBESE

Patterson B, Am J Physiol 2002

Muscle

Intestine

Liver

KidneyAdiposetissue

Tissue protein metabolism in obesity

Free AA

Intake

Ox

23%

8%

69%ProteinSynthesis ?

Balagopal P, Am J Physiol 2002

CirculatingProteins

Liver

CirculatingProteins

AcutePhase

Proteins?

AA

AA

Muscle

?MEAL

Boirie Y, Am J Clin Nutr 1997

Splanchnic extraction of dietary AA may be affected by adiposity

Liver

Muscle

Intestine

Liver

KidneyAdiposetissue

Tissue protein metabolism in obesity

Free AA

Intake

Ox

23%

8%

69%

ProteinSynthesis?

ProteinSynthesis

Changes in body and muscle composition in obesity

Increased intramyocellular lipids

Decreased oxidative capacity

Mitochondrial dysfunction

Less type 1 fibers

More glycolytic fibers (type 2)

Decreased capillary density

Beals JW, Am J Clin Nutr 2016

Murton AJ, Diabetes 2015

PostabsorptiveInsulin + AA clamp

Guillet C, JCEM 2009

Muscle Mitochondrial Protein synthesis (%/h)

R2 = 0,42

0

0.02

0.04

0.06

0.08

0.10

0.12

0 10 20 30 40 50

Mus

cle

prot

ein

synt

hesi

s(%

/h)

Fat mass (kg)

Muscle protein synthesis isaffected by adiposity?

Muscle protein synthesis isrelated to body fat mass

Stephens FB, Diabetes 2015

Basal FedIntralipid infusion

21-g bolus AA + clamp INS

increased muscle lipid availabilitymay contribute to anabolic resistance

High Fat Feeding(saturated FA)

WAT

Buffering capacity

WAT1- Reduced expandibility capacity with aging

AGING

FFA2- Muscle lipid toxicity

Reduced protein synthesis

Skeletal muscle

3- Alteration of proteinsynthesis

(phosphorylation eiF2)

IN VIVO

Protein synthesis

Skeletal muscle

Tardif N, Aging Cell 2014

Muscle protein metabolism is impaired in obesity

Reduced muscle protein turnover and lesser contribution to whole body protein metabolism

Lower muscle protein synthesis especially mitochondrial protein synthesis in response to insulin or to meal intake

Intramyocellular lipids may affect muscle proteinmetabolism by interacting on translation initiation pathways

Insulin resistance, inflammation and lipoxicity may limitprotein synthesis on a long term basis especially duringaging

Guillet C, Obes Rev 2012

Obsit et Mtabolisme protique

Trop de gras ou trop peu de maigre ?

Masse maigre, moteur du renouvellement

protique : spcificits de lobsit

Applications cliniques potentielles

Clinical conditions associated with muscle lossand obesity (sarcopenic obesity)

Hypercortisolism Diabetes Hypogonadism Long-term immobilization Chronic organ disease (CKD, COPD, HF) Cancer, neurological disorders, Weight cycling ? Bariatric surgery ?

Bariatric surgery induces muscle loss

36% of weight loss is fat free mass during 3 months, then stabilisation at about 16% from 3-6 to 12 months

c

Ciangura C, Obesity 2009

Metabolic scenarios conductive to the onset of sarcopenic obese phenotype

Young ActiveHealthy

AgingInactiveDisease

Diet ?Activity ?

Sedentarity ?Protein deficit ?

Adapted from Prado CM, Clin Nutr 2012

mechanicload

metabolicload

Insulinresistancemovement ?

anabolicgain

Energyintake

Protein deficit

Anabolic loss

Weight loss

Energy deficit

mechanicload

metabolicload

Insulinresistancemovement ?

anabolicgain

Energyintake

Protein deficit

Anabolic loss

Weight loss

Energy deficit

PROTEINS EXERCISE

Andreu, Obes Surg 2010

Ledoux S et al. Ann Surg 2014

Aron Wisnewski J, PlosOne 2013

Protein intakes and losses

Bischoff S, Nutrition 2016

PRO: 70% with >60g/dCON: 30% with >60g/d

van den Broek M, Nutr Rev 2016

Verreijen AM. Am J Clin Nutr 2015

Alverez Camero E, Obesity 2017

96 patientsRYBB

6 months EXQuartile of

stepsQ1: 4343Q2: 5175Q3: 6533Q4: 7884

Conclusions

Fat mass and fat free mass changes are not sodependent: FM/FFM ratio may be very variable among the obese population

Ectopic muscle fat accumulation promotesanabolic resistance through signalling alterations

Weight loss or gain over time may promotesarcopenic obesity development

New strategies targeting muscle anabolicresistance in obesity should be proposed

Human Nutrition research Unit

Merci

Team Diet and muscle -skeletal Health