Andreu Palau-Lo último en obesidad

Gene expression profile of programmed
obesity and its control within the leptin system
Perfil de expresión génica de la obesidad
programada y su control por la leptina
Andreu Palou
Grupo de “Nutrigenomica y Obesidad”
Centro de Investigación Biomédica en Red (CIBER) sobre Fisiopatología de la Obesidad y
Nutrición (CIBEROBN) & Laboratorio de BiologíaMolecular, Nutrición y Biotecnología (LBNB) de la
Universitat de les Illes Balears (UIB) & Alimentómica S.L. (Technologically based Spin-Off).
Campus UIB, 07122 Palma de Mallorca (SPAIN). andreu.palou@uib.es
International Symposium “LATEST IN OBESITY”
Fundación Ramón Areces & Fundación General CSIC. Madrid, December 1-2, 2015

Development is Most Important Time
to Intervene to Prevent Disease
Obesity, CVD, chronic lung disease, allergy, some cancer, cognitive decline,
osteoporosis, sarcopenia, and affective disorders, are the world’s biggest
killers.
60% of all deaths globally (WHO; Hanson & Gluckmam, 2011)
Sept. 22, 2010

Risk of non-communicable disease increases along a trajectory through the life course. The inherited
genetic variation makes only a small contribution to later risk. Adult lifestyle interventions reduce risk to
only a small degree or transiently. The maximum effect will be gained from timely interventions in early
life when plasticity permits a sustained reduction in the trajectory of risk to be attained.
(Modified from: Hanson,M., Gluckmam, P.: Developmental origins of
noncommunicable disease: population and public health implications. Am J Clin
Nutr: 94, 1754S-1758S (2011)
Fixed genetic
contribution

Laboratory of Molecular Biology, Nutrition & Biotechnology ( University
Balearic Islands, UIB)
Alimentómica SL (technologically based spin-off company)
Biomedical Center Network (Obesity and Nutrition)(CIBEROBN)
Acknowledgments
AGL2009-11277
AGL2012-33692

DEVELOPMENTAL
ORIGINS OF OBESITY
AND HEALTH
RELATED
ALTERATIONS
GENETICS
EPIGENETICS
LIFESTYLE
FOOD / NUTRITION
ENVIRONTMENT
INFLAMATION
INSULIN/LEPTIN SIGNALLING
LIVER/MUSCLE/ADIPOSE HEALTH
CELL GROWTH/DIFFERENTIATION
IMMUNE ADAPTATIONS
OVERWEIGHT
OBESITY
METABOLIC SYNDROME
PREGNANCY/LACTATION
MATERNAL
UNDERNUTRITION
DIETING
ENERGY METABOLISM
(BAT/WAT)
FOOD PATTERNS
Diets (High
Fat ; High
protein;
cafeteria)
Exercise
Bioactives
Biomarkers
Composition
Metabolism
Nutrig. tests
Cell culture
Blood cells
WAT visceral/subcutaneous
Metabolic adaptations
Post-cafeteria & false-lean
UCP1
Browning
Obesity/MS
Mild caloric restriction
Pre-pregnancy dieting
Lactating mothers
Offspring imprinting
Methylation
Metabolism, blood/saliva cells
Biomarkers
SNPs
(Humans)

About 25% of cases of obesity in
adulthood may have its origins in the
early stages of pre- and postnatal
development
Newsweek Cover (Sept 1999)

Gestation
Lactation
Programming of tissues
and organs
Persistent influence on
health
(e.g. susceptibility to
overweight/obesity)
Metabolic programming or imprinting

Early nutrition and risk of obesity in adulthood
Martorell et al., 131:874S-880S (2001)
Fetal life Perinatal period

Environmental factors: Excess food intake, less physical
exercise, lifestyle
Endogenous factors: genes (SNPs….)
Our bodies are better adapted to combat weight loss than to combat weight gain.
Man evolved as a hunter-gatherer, with periods of intense physical activity
alternating with periods of famine, and a short lifespan.
OBESITY: what are the causes ?
Specific food compounds?
Sensitive periods (development)?
Nutrients in ‘early’ life?

1. THE NEW FUNCTION OF LEPTIN: AN ESSENTIAL NUTRIENT DURING
EARLY LIFE
1. RAT MODEL: MODERATE MATERNAL CALORIC DURING LACTATION
PROTECTS OFFSPRING AGAINST OBESITY AND/OR RELATED
ALTERATIONS IN ADULTHOOD
1. RAT MODEL: MILD CALORIC RESTRICTION DURING PREGNANCY
PREDISPOSES OFFSPRING TO OBESITY AND/OR RELATED
ALTERATIONS IN ADULTHOOD
1. EARLY BIOMARKERS OF PREDISPOSITION TO OBESITY AND OF ITS
CORRIGENDUM BY LEPTIN INTAKE DURING LACTATION

1. The new function of leptin:
essential nutrient in mammals during
early life

Positional cloning of the mouse obese gene and its human
homologue. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L,
Friedman JM
Nature 372:425-432 (December 1994)
THE BODY WEIGHT CONTROL SYSTEM BEGAN TO BE UNVEILED 21
years ago…
leptin

FAT STORES
lep (ob)
Ob protein or leptin
?
CNS
ENERGY EXPENDITUREFOOD INTAKE

mice ob/ob
Absence of leptin
obese
Food intake
Energy expenditure
leptin
Halaas et al. (July 1995).. Science 269: 543
Campfield et al.(July 1995).. Science 269 546
Pelleymounter et al. (July 1995) Science 269 540

S. O'Rahilly, I. S. Farooqi. THE GENETICS OF OBESITY
Philos Trans R Soc Lond B Biol Sci. 2006; 361(1471): 1095–1105
Response to leptin
therapy in subjects
who are congenitally
deficicient in leptin

However, in general, obese are not leptin-deficient but leptin-
resistant. Plasma leptin levels are higher in obese
0
10
20
30
40
50
60
Lean Obese
Leptin(ng/ml)
*
Sinha et al. J. Clin. Invest. 97: 1344-1347, 1996
Leptin resistance
Leptin resistance: when? how?

What we eat, how we live, our feelings, etc. alters
the behavior of our genes…
The response to food intake is even different in twins
despite having identical genetics
EPIGENETIC VARIABILITY: history of food intake, habits,
adquired changes…

Confers protection against obesity in later life
Versus
?
There were increasing epidemiological evidence (e.g.: Armstrong &
Reilly, Lancet 2002; Harder et al., Am J Epidemiol, 2005) that:
Breastfeeding Formula feeding

In 2000 we found Leptin mRNA in human stomach
.
Secretory granules of endocrine and chief cells of human
stomach mucosa contain leptin
S. Cinti, R. De Matteis, C. Picó, E. Ceresi, A. Obrador and C. Maffeis, J.
Oliver, P. Oliver and A. Palou
Int J Obes 24: 789-793 (2000)

fasted patient non fasted patient
45x
1125x
Leptin in human stomach: Immunohistochemistry

Days Hours Days
Birth
0
10
20
30
40
50
60
19 20 0 2 4 8 24 4 7 15 21 30
Leptin-mRNA
1.2
0
0.2
0.4
0.6
0.8
1
19 0 8 24 4 7 15 21 30
Days Hours Days
Birth
after birth
Leptin-protein
P. Oliver, C. Picó, R. De Matteis, S. Cinti, A. Palou. Dev. Dyn. 223: 148-154, 2002
Leptin (protein) levels in the stomach are not related with
leptin mRNA levels in neonate rats
Maternal origin endogenous
Leptin is present in maternal milk
(Casabiell et al., 1997; Houseknecht
et al., 1997)

Supplementation of neonate rats with
physiological doses of leptin during the suckling period

Immunostaining for leptin in the gastric mucosa in 4-day-old rats. Leptin is mainly
located in the apex of the superficial epithelial cells. 4 h after leptin
administration,immunoreactivity is stronger than in the time 0 group
Leptin orally supplied to neonate rats is directly uptaken
by the immature stomach
Sanchez J, Oliver P, Miralles O, Ceresi E, Pico C, Palou A. 2005. Endocrinology 146:2575-82
Time 0 Time 4 h

vehicle
leptin
Serum leptin
Serumleptin(%time0)
0
50
100
150
200
250
0 1 h 4 h
Time after treatment
a
b
a, c
c
a
L
L=Effect of leptin treatment
… is transferred to the bloodstream …
a≠b≠c≠d
Sánchez, Oliver, Miralles, Ceresi, Picó, Palou. Endocrinology 146: 2575-82, 2005

Stomach of 2 days
Inmunohistochemistry for leptin in rat stomach

Stomach of 21 days

Contrary to breast milk there is no human leptin
in infant formulae …
Yes !!!

 Direct evidence from
intervention studies in rats
Palou et al. (Feb 2005) (patent);
Int J Obesity 31: 1199-1209 (2007)

0
100
200
300
400
500
600
0 30 60 90 120 150 180
days
bodyweight(g)
control
leptin
A daily oral dose of leptin during lactation protects against overweight in
adulthood (under normal fat diet)
Picó, Oliver, Sánchez, Miralles, Caimari, Priego, Palou. Int J Obesity 31: 1199-1209, 2007
(Normal fat diet)
LEPTIN
SUPPLEMENT
Physiological
oral dose

0
100
200
300
400
500
600
0 30 60 90 120 150 180
days
bodyweight(g)
… and also under high fat diet
Picó, Oliver, Sánchez, Miralles, Caimari, Priego, Palou. Int J Obesity 31: 1199-1209, 2007
(High fat diet)
control
leptin
(Normal fat diet)
control
leptin
LEPTIN
SUPPLEMENT
LEPTIN
SUPPLEMENT
Physiological
oral dose

Indirect evidence in humans…

Breast milk leptin levels were negatively
correlated with body weight gain of infants until
2 years of age
r = - 0.575
P < 0.01
24 months of age
0
2
4
6
8
10
12
14
0 0.1 0.2 0.3 0.4
Breast milk leptin (ng/mL)
Bodyweightgain(kg)
Miralles, Sánchez, Palou, Picó. Obesity 14: 1371-1377, 2006
Age: 31.2  0.7 years
BMI: 21.6  0.5 kg/m2
28 non-obese mothers
Moderate amounts of milk-borne maternal leptin appear to provide moderate
protection to infants from an excess of body weight
CONFIRMED BY OTHER INDEPENDENT GROUPS:
Doneray H, Orbak Z, Yildiz L (2009). The relationship between breast milk leptin and neonatal
weight gain. Acta Paediatr 98:643-647
Schuster S, Hechler C, Gebauer C, Kiess W, and Kratzsch J (2011). Leptin in Maternal Serum
and Breast Milk: Association With Infants’ Body Weight Gain in a Longitudinal Study Over 6
Months of Lactation. Pediatr Res 70: 633–637

A number of processes affected in the long term…(rats up to 15 months of age)
Improvement of
LEPTIN (ANOREXIGENIC) SENSITIVITY
INSULIN SENSITIVITY
FOOD PREFERENCES
NAFLD
…

Hepatic lipid content
Response to a HF diet
0
20
40
60
80
100
Control Leptin
%vsNFfedcontrol
*
*
 80%
 38%
ANOVA L, D
NF-diet
HF-diet
Leptin-treatment ameliorated HF
diet-induced hepatic fat
accumulation occurring in control
animals
Liver
Priego T, Sánchez J, Palou A, Picó C
International Journal of Obesity (2010) 34, 809–819

Mechanisms: The responsiveness of the hypothalamus to the food intake inhibitory
effect of leptin depends on factors determining leptin sensitivity: increase of LepR
and decrease of SOCS-3 (Picó et al. Int J Obesity 2007)
OB-Rb: leptin receptor
SOCS-3: suppressor of cytokine signaling 3
SOCS-3
LepR
Breast milk Leptin prevents age-related loss of central
sensitivity to leptin

NATURE REVIEWS GASTROENTEROLOGY AND HEPATOLOGY 7, 359 (July
2010)
UP REGULATION OF LEPTIN RECEPTOR ALSO IN PERIPHERAL TISSUES

Animals supplemented with oral leptin during
lactation become more protected against
obesity/overweight appearance in adult life, and
are more sensitive to leptin signalling
CONCLUSION

2. Rat model: moderate (20-30%)
maternal caloric restriction during
lactation protects offspring against
obesity and/or related alterations in
adulthood
PHYSIOLOGICAL CONDITIONS LEADING TO HIGHER/LOWER PREDISPOSITION TO
OBESITY AND OTHER METABOLIC ALTERATIONS ARE RELATED TO THE INTAKE OF
LEPTIN DURING LACTATION: “caloric restriction models”

Rats from dams submitted to moderate calorie restriction (CRL)
during lactation
0
50
100
150
200
250
300
350
400
450
0 10 20 30 40 50 60 70 80 90 100 110
Age (days)
bodyweight(g)
CONTROL
CRL
CONTROL
CRL
♂
♀
M. Palou, T. Priego, J. Sánchez, JM Torrens, A. Palou, C. Picó. Endocrinology, 2010
 These animals are protected against
overweight in adulthood
This treatment also:
 Improves capacity to control body
weight under dietary stressors such as HF-
diet feeding
 Improves leptin and insulin sensitivity
 Protects against the development of
dyslipidemia and hepatic steatosis
Model of
“improved metabolic health”

Moderate Caloric Restriction in Lactating Rats Protects Offspring
against Obesity and Insulin Resistance in Later Life.
Palou M, Priego T, Sanchez J, Torrens JM, Palou A, Picó C. Endocrinology 151: 1030–1041, 2010.
HOMA-IR

Moderate Caloric Restriction in Lactating Rats Protects Offspring against Obesity
and Insulin Resistance in Later Life.
Palou M, Priego T, Sanchez J, Torrens JM, Palou A, Picó C. Endocrinology 151: 1030–1041, 2010.
LEPTIN IN MAMMARY GLAND IS MORE EXPRESSED IN CALORIC RESTRICTED DAMS

3. In a rat model, contrary to what
happens in lactation: mild caloric
restriction of the mothers during
pregnancy predisposes offspring to
develop obesity and/or related
alterations when adulthood
Are there nutritional factors or conditions, which enhance the
predisposition to obesity ?
THIS PREDISPOSITION CAN BE REVERTED BY THE
ORAL INTAKE OF LEPTIN DURING LACTATION

Dutch famine during the 2nd World War
EXPOSURE OF MOTHERS DURING THEIR 1st HALF OF PREGNANCY
SEVERE ENERGY RESTRICTION DURING PREGNANCY
(Background of Epidemiological Studies in Humans)

Dutch Famine
300.000 men
19 year old
3er trimester
2nd trimester
1st trimester
severe malnutrition
Ravelli GP et al (1976) Obesity in young men after famine exposure in utero and early
infancy. N. Engl. J. Med. 295: 349 –353
Gestational Caloric Restriction and Predisposition of
Offspring to Obesity
The men who were conceived
during the last 6 months of the
2nd World War and whose
mothers experienced poor
nutrition in the 1st and 2nd
trimester of pregnancy were
more likely to suffer obesity
OBESITY

…and there are several animal studies showing a metabolic programming
of obesity by severe restriction (caloric, proteic…) during pregnancy
(References in: Picó et al.: Front Physiol 3, 436, 2012)
Low birth weight
Overweight
in adulthood
severe caloric
restriction

Mild calorie restriction (20%) during pregnancy in rat dams results in
higher body weight (and fat) in the offspring (only in males)
Age(days)
Bodyweight(g)
CR males
Control males
CR females
Control females
;
#
0
50
100
150
200
250
300
350
400
450
500
550
0 15 30 45 60 75 90 105 120 135 150 165)
(g)
CR
Control
;
#
0
50
100
150
200
250
300
350
400
450
500
550
0 15 30 45 60 75 90 105 120 135 150 165
High fat diet
M. Palou, T. Priego, J. Sánchez, A. Palou, C. Picó. Nutrition & Metabolism (2010)
Both males and females showed higher food intake, insulin resistance
and leptin resistance when adults
Normal fat diet

2 months 4 months 5 months
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
HOMA-IR
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0
8.0
ANOVA:
R
S
#
HOMA-IR
ANOVA:
R
S
0.0
1.0
2.0
3.0
4.0
5.0
6.0
7.0 #
HOMA-IR
Control
CR
NF diet HF diet
Food intake increase in CR animals is associated to less
sensitivity to insulin
HOMA index
M. Palou, T. Priego, J, Sánchez, A. Palou, C. Picó. Nutrition & Metabolism (2010)
females malesmales femalesmales females

Which mechanisms could be
responsible of these alterations?

Females
CR
C
* vs controles (p<0,05; t test)
100µm
hematoxilin/eosin
staining
Males
The offspring of calorie-restricted rats during gestation already showed
alterations in hypothalamic structures involved in food intake control
25 days old
Hipothalamus
Arcuate nucleus
Number of cells
A.P. García, M. Palou, T. Priego, J. Sánchez, A. Palou, C. Picó. Diabetes, obesity and metabolism, 12: 403-413, 2010
0
200
400
600
800
1000
R
*
 3%
 18%
FemalesMales
numberofcells
Anova
C
CR

0
25
50
75
100
125
150
175
200
Males Females
C
CR
R
%vsmachoscontrol
* Anova
0
20
40
60
80
100
120
140
160
180
200
Males Females
C
CR
S
R
%vsmachoscontrol
* Anova
0
25
50
75
100
125
150
175
200
225
250
275
Males Females
C
CR
R
%vsmachoscontrol
Anova
S, R: efect of sex or caloric restriction, two
ways anova (p<0.05)
*vs control t-test p<0.05
A.P. García, M. Palou, T. Priego, J. Sánchez, A. Palou, C. Picó. Diabetes, obesity and metabolism, 12: 403-413, 2010
SOCS-3: Suppressor of
cytokine signaling 3
H y p o t h a l a m u s
… and showed impaired leptin and insulin signaling
That may explain the disregulation of food intake that show these animals
Leptin receptor (mRNA) Insulin receptor (mRNA)
SOCS-3 (mRNA)
25 days old

C CR
Inguinal WAT
25-day-old rats
AP García, M Palou, J Sánchez, T Priego, A Palou, C Picó. PLoS ONE, 2011
WAT sympathetic innervation
(TH+ area/section)
0
5
10
15
20
25
30
MALES
Control CR
*
µm2/mm2
TH : tyrosine hydroxylase
… In addition, male offspring of
calorie restricted dams during
gestation showed lower WAT
sympathetic innervation, which can
explain the hyperplasia and higher fat
accumulation occurring in WAT in
adulthood

0
20
40
60
80
100
120
140
Males Females
%vsControlmales *
ANOVA R,S
BAT sympathetic innervation
(Protein levels of TH)
25 days
Brown adipose tissue is also less innervated
TH, tyrosine hydroxylase;
R, effect of calorie restriction; S, effect of sex;
(p<0.05, two-way ANOVA);
*, CR vs Control (p<0.05; Student’s t test).
Palou, Priego, Romero, Szostaczuk, Konieczna, Cabrer, Remesar, Palou, Picó. Int J Obes, 39:339, 2015
UCP1 levels
0
20
40
60
80
100
120
ANOVA R,S
%vsControlmales
21.3%
16.9%
Males Females
Lower thermogenic capacity
that may contribute to the
greater propensity to obesity
C
CR

Bouret SG et al;
Clinical Genetics 2006
 Neurotrophic action of leptin during early development on hypothalamic circuits
involved in the control of food intake
Males and Females: AxR
(3-way ANOVA)
Males
CR
0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
Control
a
b
a
Leptin(g/l)
CR
d6
d9
d15
Females
Control
a
b
a,b
The offspring of calorie restricted dams
during gestation did not show the transient
increase in circulating levels of leptin during
the suckling period that occurred in control
animals
“leptin surge”
establishment of neuronal projections from the
arcuate nucleus to other areas of the
hypothalamus

Developmental programming of:
- Energy balance
- Leptin/insulin sensitivity
- Eating behaviour
- Body composition
Energy restriction during pregnancy
Increased susceptibility to obesity and
related metabolic alterations
Outcome
Adapted from: C. Picó, M. Palou, T. Priego, J. Sánchez, A. Palou. Frontiers in Physiology 3, 2012
Early life
Adult life

Experimental Design
CR
CR -Leptin
TREATMENT
Gestation
Caloric
Restriction (20%)
d1 to d12
BirthPregnancy
Gestation
Pregnancy Birth
Control
Lactation
vehicle
d1 to d20
Lactation
Lactation
vehicle
d1 to d20
Leptin
d1 to d20
Sacrifice
day 21
Control, CR and
CR-Leptin group
fed
Western Diet
Control, CR and
CR-Leptin group
fed
Standard Diet
Standard diet
Weaning
month 4 month 6
SAMPLING
Day 25

0
20
40
60
80
100
120
140
Males Females
Numberofcells(n)
NPY+ cells
b
a a,b
FemalesMales
3v
ARCARC
3v
ARCARC
3v
ARCARC
3v
ARCARC
3v
ARCARC
3v
ARCARC
100µm
CR-Leptin
CR
Control
50µm
Control
CR
25 days
Control
CR
CR-Leptin
TyrOH
β-actin
CR-Leptin
s
Control
CR
CR-Leptin
TyrOH
β-actin
CR-Leptin
Control
CR
CR-Leptin
Oral treatment with physiological doses of leptin during the suckling period largely
reverses the adverse effects of calorie restriction
J. Konieczna, A. P. García, J. Sánchez, M. Palou, A. Palou, C. Picó. PLoS ONE 8(11), 2013
0
20
40
60
80
100
120
140
Males Females
Numberofcells(n)
NPY+ cells
b
a a,b
FemalesMales
3v
ARCARC
3v
ARCARC
3v
ARCARC
3v
ARCARC
3v
ARCARC
3v
ARCARC
100µm
CR-Leptin
CR
Control
50µm
CR-Leptin
Leptin treatment restores the number
of NPY+ neurons, that were diminished
in CR male animals
Caloric Restriction: structural and functional changes of the hypothalamus

Figure 4. Hypothalamic expression levels of AgRP, CART, NPY, ObRb, POMC and SOCS-3 in 25-day-old male and female offspring of dams with
free access to standard chow diet (controls), the offspring of 20% calorie restricted dams during the first 12 days of pregnancy (CR), and CR
rats daily supplemented with physiological doses of leptin throughout lactation (CR-Leptin). mRNA levels were measured by qRT-PCR and
expressed as a percentage of the value of control male rats. Data are mean ± S.E.M. (n = 10-11, coming from at least six different litters).
Gene expression levels in the hypothalamus

Males Females
0
100
200
300
400
a
b
a
Two-way ANOVA: NS
%vsControlMales
Control
TyrOH60 kDa
β-actin42 kDa
CR Control CRCR-Leptin CR-Leptin
TyrOH/β-actin levels measured by Western Blot
20µm
20µm
20µm
CR-Leptin
Control
CR
25
daysControl
CR
CR-Leptin
TyrOH
β-actin
CR-Leptin
s
Control
CR
CR-Leptin
TyrOH
β-actin
CR-Leptin
♂ ♀
Control
CR
CR-Leptin
Leptin treatment also recuperates WAT sympathetic innervation that was
altered in CR male rats
Sympathetic innervation
J. Konieczna, M. Palou, J. Sánchez, C. Picó, A. Palou. Int. J. Obes., 2015

In summary, Programmed alterations in the offspring caused by
a mild (20%) caloric restriction of mothers during 1st half of
pregnancy, which are recovered by the oral intake of leptin
during suckling (Palou et al., 2005-2015)
CALORIC RESTRICTION
Energy balance (food intake)
Leptin sensitivity
Insulin sensitivity
Eating behavior
CVD risk factors
Fatty liver
…
Sympathetic inervations of adipose
tissue
Number nerurons in the
hypothalamus
Gene expression changes
…
CALORIC RESTRICTION
(+ LEPTIN)
Energy balance (food intake)
Leptin sensitivity
Insulin sensitivity
Eating behavior
CVD risk factors
Fatty liver
…
Sympathetic inervations of
adipose tissue
Number nerurons in the
hypothalamus
Gene expression changes
…

Koletzko et al., 2005
Breastfeeding reduces the risk of
overweight/obesity by ≈ 20-25 %
4. ARE THERE EARLY (feasible, reproducible,
suitable, affordable,…) BIOMARKERS OF THESE
IMPRINTED OBESITIES ?

Leptin
Stomach
-
+
Summarizing the metabolic programming protective role of
leptin intake from breast milk in lactating offspring
Afferent
signalling
LepR
LepR
Leptin
LepR
Adipose and other
tissues
Master Gene(s)?
Multiple effects
BIOMARKERS IN
BLOOD CELLS
Gene expression
Orexigenic
peptides (NPY, AgRP)
Food intake
Energy expenditure
Anorexigenic
peptides (POMC/MSH, CART)
Food intake
Energy expenditure
+
-
Control of Energy Balance
Leptin sensitivity
Short / Long
Term

CANDIDATE
APPROACH
OMICS
APPROACH
fto, rxr, cpt1, fas, pomc, npy, lep, lepR, b3ar, ucp1, pparg, cebpa, ins,
cck, prb, scdh, acc, rar, ….irx3
rxr, cpt1,
fas,pomc,
npy, lep,
lepR,
b3ar,
ucp1,
Ja, ja,
ja…UAU!!!
Peripheral blood cells (PBMCs)

White blood cells including:
lymphocytes
monocytes
 easily and repeatedly collected in
humans
 travel through the body responding to
internal and external signals (as dietary
modifications)
 previous studies show PBMCs reflect
changes in gene expression that occur
in other tissues (WAT, liver)
GENE EXPRESSION PROFILING
IN PBMCs
Approach to develop
biomarkers of obesity
Peripheral blood mononuclear cells (PBMCs)
as a source of biomarkers

3
2
2
1
1
1
2
5
3
5
3
2
2
6
6
3
7
4
4
1
1
4
3
4
4
5
3
6
5
7
11
13
14
14
20
18
29
0 5 10 15 20 25 30 35
Others
Metabolism (redox)
Metabolism (central)
Metabolism (nucleotides)
Epigenetic modification
Metabolism (carbohydrates)
Blood
Cell communication
Neural signaling
Nervous system
Sensory perception
Cytoskeleton
Metabolism (lipids)
Transport
Metabolism (proteins and polyamines)
Cell turnover
Signaling
Immune system
Transcription/translation machinery
Number of genes
Process
Downregulated
Upregulated
224 known genes
Classification into biological processes of
genes differently expressed in PBMCs
Mild (20%) maternal calorie restriction during pregnancy affected the
expression levels in PBMCs of 224 genes compared to controls
25 days
Male CR rats vs controls (p≤0.010 )
J. Konieczna, J. Sánchez, M. Palou, C. Picó, A. Palou. Sci Rep, 5: 9088, 2015

CONTROL CR CR-Leptin
heat-map
Individual expression
pattern of the 224 genes
differently expressed
between control and CR
animals
J. Konieczna, J. Sánchez, M. Palou,
C. Picó, A. Palou. Sci Rep, 5: 9088, 2015
Green: underexpression
Red: overexpression

CONTROL CR CR-Leptin
heat-map
Individual expression
pattern of the 224 genes
differently expressed
between control and CR
animals
Green: underexpression
Red: overexpression
J. Konieczna, J. Sánchez, M. Palou,
C. Picó, A. Palou. Sci Rep, 5: 9088, 2015
Candidates as early
BIOMARKERS

Usefulness of early biomarkers
 Select subjects at early age who are at greater risk of developing obesity
and other pathologies, and whose alterations could be reverted by the
intake of adequate amounts of leptin during lactation
 Monitor the reversion of the increased risk

Thank you very much for your
attention
Acknowledgments
AGL2009-11277
AGL2012-33692

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