The First 1000 Days of Life:

Thriftiness and Energy Metabolism

Safarina G. Malik
Eijkman Institute for Molecular Biology
Jl Diponegoro 69, Jakarta 10430, Indonesia
ina@eijkman.go.id
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 Why is it important??

• Fetus reacts to its unique environment, with profound

consequences for later life
• Undernutrition will lead to susceptibility to non-communicable
disease
• IUGR newborns demonstrate an enhanced susceptibility to
obesity and metabolic abnormalities in response to a high-fat
diet
• Rapid catch-up weight gain lead to the development of insulin
resistance, associated with accumulation of central abdominal
fat mass

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 Thrifty phenotype hypothesis
(Hales & Barker 2001)

• An adverse prenatal events that caused differential

gene expression, resulting in a phenotype that is better
suited, metabolically, for a deprived environment.
• A malnourished mother has an increased propensity to
give birth to offspring that feature a "thrifty
phenotype" which permits highly efficient calorie
utilization, increased fat deposition and a sedentary
nature.
• It assumes that some components of growth are
selectively sacrificed to preserve more critical
outcomes, like the brain (Barker, 1998; Giussani, 2011)
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 Thrifty phenotype hypothesis
(Hales and Barker, 1992)

The ‘‘thrifty phenotype’’ was modified by nutrition during fetal

development

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Ozanne,and Hales 2002
Fetal adaptations to undernutrition: a framework

Barker, 2001
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 Intergenerational effects of intra-uterine growth
retardation and gestational diabetes in causing T2D in
non-industrialised countries

Fall, 2001

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 Thrifty genotype hypothesis
Neels, 1962

• Thrifty genotype was selected by famine during evolution,

which demanded more energy storage capacity and efficient
energy metabolism
• People with thrifty genotype could store fat better than others
could, therefore were more likely to survive prolonged food
shortages
• Lifestyle-related SNPs hypothesized as thrifty genotype
comprise SNPs of nDNA and mtDNA. Some of these SNPs
promote development of obesity and T2DM
• In affluent societies thrifty genotype that saves energy,
becomes disadvantageous, leading to a higher risk of
developing obesity and CVD

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 Mitochondria and Mitochondrial DNA
• Mitochondria – fulfill both hypothesis:
• Mitochondrial function - thrifty phenotype
• Mitochondrial genome and mtDNA SNPs - thrifty genotype
• Mitochondria is modulated by changes in pattern of energy
metabolism in respond to in-utero environment

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 Human Evolution, MtDNA and Agriculture
Mediterranean agriculture Tropical agriculture
barley pea beet wheat cattle: SFA rice sugarcane taro yam banana

High protein Thermogenesis Low protein

High fat C,D A A* Low fat
H,T,U,V,W,X 7,000 – 9,000
I,J,K G yBP
40,000 – A* A,C,D
50,000 yBP B B
N
* 26,000 –
N F 12,000 – 34,000 yBP fish: DHA
M 15,000 yBP
L1 L3
low salt L2 60,000 –
130,000 – 70,000 yBP A,C,D
170,000 yBP Starvation Starvation
70,000 yBP B

Low protein Low protein

Low fat Low fat
beans millet gourd sesame potato string beans pumpkin corn
Savannah agriculture New world agriculture
Evolution of H. sapiens deduced from mtDNA, and 4 major agricultures
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(Modified from Kagawa et al, 2002)
 Human migrations and metabolic adaptation to
different environmental stressors: a new theory for
ethnic obesity variation

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Sellayah, et al. Endocrinology, 2014:doi: 10.1210en.2013-2113 10
 MITOCHONDRIA
• Power plant of the cell ~ essential for
cell viability and survival
• Energy production: produce 1 kg
ATP/kg body weight/24 h ~ 90%
energy
• The site of oxidative phosphorylation
(OXPHOS)
• Three factors can perturb
mitochondrial bioenergetics and
result in disease: 1) variation in the
mtDNA sequence,2) variation in the
sequences of nDNA-coded
mitochondrial genes or in the
expression of these genes, or 3)
variation in environmental calories
and the caloric demands made on
Wallace DC, J Clin Invest 2013
the organism

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 MtDNA copy number (mtDNA-CN) reflects
mitochondrial biogenesis and function

• Mitochondrial genome encodes 37 genes

• Present in multiple copies – mtDNA copy number (mtDNA-CN)
• D-loop  control region for replication and transcription

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 The Role of Mitochondria in Pregnancy
• Function:
• Energy production
• Progesterone biosynthesis
• Oxygen sensing mechanisms in response to hypoxia
• MtDNA copy number in IUGR pregnancy:
• Mitochondrial abundance may be associated with placental
insufficiency, intrauterine growth restriction and preeclampsia (Lattuada
et al, Placenta 2008; Colleoni et al, Am J Obstet Gynaecol 2010; Qiu et al, Int J Mol
Epidemiol Genet 2013)
• Calorie restriction promotes the mitochondrial biogenesis (Nisoli et al.
2005)  increased mtDNA content in IUGR pregnancy is a result of the
metabolic placental adaptation to calorie restriction of the fetus
• Maternal whole blood mtDNA copy number is a novel biomarker of
systemic cellular oxidative stress and mitochondrial dysfunction
(Williams et al, Int J Mol Epidemiol Genet 2013)
• MtDNA variant T16189C:
• Associated with size at birth (Casteels et al., 1999)
• Closely located to origin of replication – associated with decreased
mtDNA copy number in peripheral blood cells (Liou et al., 2010)
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 Mitochondrial efficiency hypothesis

• Ancestral changes in mitochondrial coupling efficiency

enhanced successful adaptation of South Asians to
environmental stressors by maximizing the conversion of
energy to adenosine triphosphate (ATP) rather than heat
• But disadvantageous when South Asians are physically
inactive and consume high-caloric diets

Outline of the mitochondrial energy efficiency hypothesis and its

influence on health outcomes (Bhopal, 2009)
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Birth weight is influenced by maternal mtDNA-CN;
high mtDNA-CN is associated with LBW
(Priliani et al, Placenta 70, 2018)

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 Pregnancy is associated with increased placental
mitochondrial activity and increased mtDNA-CN

CoQ10 level increased significantly from

first trimester to third trimester but MtDNA-CN is increased as pregnancy
decreased after delivery (Matsuzaki et al, progress (Priliani et al, J Nutr, 2019)
Biosci Trends 8, 2014)
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 MMN supplementation stabilized mtDNA-CN
during pregnancy
(Priliani et al, J Nutr, 2019)

(A) low baseline mtDNA-CN

(B) high baseline mtDNA-CN

(C) duration <33 d

(D) duration ≥33 d

Commentary by Lee, Fenech, West Jr, J Nutr, 2019:

The study by Priliani et al. provides initial supportive evidence for the hypothesis that
antenatal MM supplementation may improve mt efficiency and function during
pregnancy, offering a plausible bioenergetics pathway by which birth weight could
increase via improved micronutrient nutriture.
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 MMN supplementation support more efficient
mitochondrial function, and thereby stabilizing mtDNA-CN
Sagun et al, FASEB J 19, • Vitamin C protects mtDNA from oxidative
2005 damage by reactive oxygen species (ROS)

Parikh et al, Curr Treat • Riboflavin is needed to increase the activity of

Options Neurol 11, 2009 mitochondrial complex I and II
• A combination of vitamins C and E
Cederberg et al, Pediatr Res
supplementation decreased oxidative stress
49, 2001
and improved fetal outcomes
Shankar and Prasad, Am J
• Zinc is the cofactor for antioxidant enzymes
Clin Nutr 68, 1998

Horn and Barrientos, IUBMB • Copper is needed for mitochondrial

Life 60, 2008 cytochrome c oxidase activity

Cuellar-Rufino et al, Nutr

• Iodine is associated with oxidative stress
Hosp 34, 2017

Maleki et al, Hypertens • Selenium is the cofactor for glutathione

Pregnancy
19/11/202030, 2011 peroxidase antioxidant enzyme 18
 Conclusions
• Maternal peripheral blood mtDNA-CN during pregnancy
is associated with BW.
• As pregnancy progress, the energy demands and
oxidative stress both increase.
• Lower mtDNA-CN in MMN group indicates mitochondrial
function is more sufficient and efficient.
• Maternal mtDNA-CN may be a useful index to assess risk
for LBW, and provide an early window of opportunity to
improve pregnancy outcomes.
• MMN supplementation may improve mitochondrial
function, reduce oxidative stress, stabilize mtDNA-CN,
and improve fetal growth, birth weight, and survival.

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Picture: Odra Noel, scientific artist
Acknowledgements
Eijkman Institute for Molecular Biology
Lidwina Priliani
Sukma Oktavianthi
Clarissa Asha Febinia
Restuadi Restuadi
Hidayat Trimarsanto
Badru Kamal

SUMMIT Institute of Development

Anuraj Shankar
Elizabeth Prado
Mandri Apriatni

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 The 3rd Biennial Congress of
Asia Pacific Nutrigenetics & Nutrigenomics Organization
(APNNO 2020)
1-2 December 2020

Virtual On-Line
Conference
https://www.apnno.com/biennial-conference
 http://apccn2020.com/

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 Gene hunter @ Eijkman Institute

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