El diseo actual del organismo humano, y de nuestra

alimentacin, es el resultado de millones de aos de

evolucin

Nuestros genes estan adaptados a las condiciones de vida y

de alimentacin que experimentaron nuestros ancestros

Realmente somos portadores de un

GENOTIPO PALEOLITICO

Ardipithecus ramidus
Raiz de los simios terrestres

4.5 millones de aos

Ningun animal es capaz de desarrollar enzimas que digieran la

hierba

Hojas
Tallos
Raices
Frutas

Disponibilidad
constante de
alimentos y
moderada
actividad fsica

Tallos tiernos,
roedores, insectos

Colon fermentativo

Centro del
hambre

Catecolaminas

Estomago vacio
Hipoglucemia

Centro de la saciedad

+
hambre

+
Ingestion de alimento

saciedad

Serotonina
Estomago lleno
Hiperglucemia

ADIPOQUINAS

ADIPONECTINA Y LEPTINA

Salvese quien pueda

Cambios astrologicos y
astronmicos iniciaron
una gran sequa en el este
de africa

Australopitecus Arafensis
Lucy

1. Bipedestacin

Lucy

Homo erectus

Homo sapiens

2. Perdida de los colmillos

Nio de Taung
Australopithecus africanus
3 mA

Single nucleotide polymorphisms of thrifty genes for energy metabolism:

evolutionary origins and prospects for intervention to prevent obesity-related
diseases
Yasuo Kagawaa, b, , , Yoshiko Yanagisawaa, Kyoko Hasegawac, Hisano Suzukid, Kazuto Yasudad, Hideki Kudod, Mieko Abea, Sanae Matsudad,
2002
Yuko Ishikawad, Noriko Tsuchiyad, Aya Satoa, b, Kazuo Umetsue, Yoshiko Kagawad

Targeting lipid signalling in disease

Matthias P. Wymann, Thomas Rckle, Christian Rommel,
Matthias Schwarz and Roger Schneiter
Lipids are important mediators in cancer and inflammation, and in
cardiovascular, degenerative and metabolic disease. A complex
proteinlipid interaction network comprising phosphoinositides,
sphingolipids, steroids and other lipid-derived mediators has been
uncovered over the past few years. Many of the signalling lipids may
directly interact with intracellular effector proteins to trigger multiple
High-intensity colour indicates
activity of signalling pathway
in disease:
PI3K, mTOR

TNF

N
P

SM

)P 2
4,5

s(

Syk

p85

SH2 SH2

PI3Kc

Fy n
7

PI3
K

3,4,5
)P3

P
P

P
P

Ptd
Ins(

6 9

PGs
22

Btk

S
PLC H2


LTs

5-LO
2S
Rh
o

GE

mT
OR
C2

Rho

mTORC1

Cyto
PK
kin
C
esi
s
Proli
fer
ati
27
on
ER

40

14 15

PGH

28

ER

16

T3

20
21

p85

PI3K

S47
3

18 19

08

PD

K1

24

P
P

PK

25

5)P
,4,
s(3
dIn
Pt
2

,5)P
Ins(
4

S6K

Inflammation

JN

ty
tili
Mo



C
IKK

JNK

PK

PKC 
PKC

IgE
FcRI

)P 3

SH2

12

DA

SHIP1

AA

B
-
NF

PPAR

G
DA

PPA

TG

Phosphate

SH2 SH2 domain

C1 C1 domain
C2 C2 domain
Inhibitor/antagonist
Activator/agonist

Activation
Inhibition
Indirect action

NSD

OH

et
FFA
ab
C
oli OO
cd
ise
Translocation
ase
Conversion

TLR4

Cer

TNF

n
gra
De

GP

DD

PH domain
pTyr
pTyr-X-X-Met

C

PL

OH

F1
/IG
Ig-like domain

FAB
P

Ins

Key:

CR

IK
K
CO FFA
O

Adenosine
Chemokines 55
Bacterial peptides
Eicosanoids
Prostanoids 43 44

n
tio
ula

Cer

45 46 47 48 49 50
51 52 53 54 55

Leukotrienes 35 36
Extracellular
lipid-modifying
enzymes 3 11 17

Migration of macrophages
to adipose tissue

Giripladib (PLA-695)
CPR-1006

1 Inflammation (Phase II)

2 (discovery)

Hormonesensitive lipase
nSMase
nSMase

Inhibitor

Orlistat

3 Metabolic disease (launched)

Selective inhibitor
Inhibitor

Cpd 24
SR33557

3
4

PI3KG/D

Dual inhibitor

TG100-115

PI3KG

Selective inhibitor

AS-252424

4 (discovery)
5 Hypertension, inflammation
(Phase I)
6 Inflammation, cardiac disease
(Phase I)
7 Inflammation (preclinical)

PI3KB

Selective inhibitor

TGX-221

8 Thromboembolism (preclinical)

IC87114

9
10
11
12
13
14

For a list of references and an

expanded table, see:
www.nature.com/nrm/
posters/lipidsignalling-disease

BEZ235
SC-57461A
AQX-MN100
SK-II
Diclofenac
Celecoxib
Zileuton
2ccPA 16:1

Indication (status)

Inflammation, cancer (preclinical)

Refs
1
2

5
6
8

Cancer (Phase I/II)

Inflammation (preclinical)
(discovery)
(discovery)
Inflammation (launched)
15 Inflammation (launched)
16 Inflammation (launched)
17 (discovery)

9
10
11
12

13

A-443654

18 Cancer (preclinical)

14

Cpd 13b

19 Cancer (discovery)

15

Inhibitor (allosteric binding) Cpd 14f

20 Cancer (discovery)

15

Inhibitor (phospholipid
binding)
Selective inhibitor
Selective inhibitor

Perifosine

21 Cancer (Phase I/II)

16

Inhibitor

ERA

22 Inflammation (preclinical)
Cpd 1
LY-333531, ruboxistaurin 23 Metabolic disease (preregistered)

17
18

Vernalis

24 Cancer, inflammation (preclinical)

19

SERM
SERM new generation
Synthetic selective agonist

Tamoxifen
Lasofoxifene
PPT

25 Cancer (launched)
26 Inflammation (preregistered)
27 (preclinical)

20

ERB

Synthetic selective agonist

21

Agonist
Homodimer antagonist
Selective antagonist

WAY-202041,
ERB-041 (prinaberel)
SR11237
HX51
R0-41-5253

28 Inflammation (Phase II)

RXR
RXR

29 (discovery)
30 (discovery)
31 Inflammation, cancer (preclinical)

22
23
24

Selective antagonist

LE135

32 (discovery)

25

Selective agonist
Selective agonist

Am80 (tamibarotene)
R-667 (RO-3300074)

33 Cancer, inflammation (launched)

34 Inflammation (Phase II)

LXRB

Antagonist
Antagonist
Dual agonist
Selective agonist

ICI-204219, zafirlukast
CP-195543
GW3965
Cpd 3

35 Inflammation (launched)
36 Inflammation (Phase II)
37 Metabolic disease (preclinical)
38 (discovery)

PPARG

Agonist

Rosiglitazone

39 Metabolic disease (launched)

PPARA

Agonist

Cpd 36

40 (preclinical)

32

PPARD
PPAR
DP2/TP receptors
DP1 receptor
DP2 receptor

Agonist

GW501516

41 Metabolic disease (Phase II)

33

Pan agonist
Dual antagonist
Antagonist
Agonist

Cpd 34r
Ramatroban
MK-052, laropiprant
DK-PGD2

42 Metabolic disease (preclinical)

43 Inflammation (launched)
44 Inflammation (Phase III)
45 (discovery)

34

35
36

DP2 receptor
EP1 receptor
EP2 receptor
EP3 receptor
FP receptor
FP receptor
IP receptor
IP receptor

Antagonist
Antagonist
Selective agonist
Selective agonist
Agonist
Antagonist
Agonist
Antagonist

TM30089
GW-848687X
CP-533,536
M&B-28767
Latanoprost
AS-604872
Cicaprost, ZK-96480
RO-1138452

46 (discovery)
47 Inflammation (preclinical)
48 Inflammation (preclinical)
49 Inflammation (preclinical)
50 Glaucoma (launched)
51 Premature labour (preclinical)
52 (Phase II discontinued)
53 Cardiovascular disease,
inflammation (preclinical)
54 Cardiovascular disease (Phase III)
55 (discovery)

37
38
39
40

41
42
43

Btk

,5
s(3,4

P
P

29

8
37 3

LXR

Cer

41 42

PP 9
AR


2+
Ca

2+
Ca

1
2
cPLA

31
3

34

rK

RA

Ce

Growth

O
N

Compound

PKBB
PKB

PtdIn

33

Ce

hesis
synt
ein
rot

23

FK

)P
(3,4
Ins
Ptd

RC1

mTO

C2
C1 KC
P

Ptd

OH

8 10

2
P1

NH

30

GF

P
P
P ,5)P 3
4
(1,

p
Ra

Sph

Caspase cascade,
apoptosis

ROS
ER stress

About Merck Serono

Merck Serono, the new division for innovative small molecules and
biopharmaceuticals of Merck, was established following the
acquisition of Serono and the integration of its business with the
former Merck Ethicals division. Headquartered in Geneva,
Switzerland, Merck Serono discovers, develops, produces and
commercializes innovative products to help patients with diseases
with unmet needs. Our North American business operates in the
United States and Canada under EMD Serono.
Merck Serono has leading brands serving patients with cancer
(Erbitux), multiple sclerosis (Rebif), infertility (Gonal-f),
metabolic and cardiometabolic disorders (Glucophage, Concor,
Saizen, Serostim), as well as psoriasis (Raptiva). With an annual
R&D investment of 1bn, we are committed to growing our
business in specialist-focused therapeutic areas, such as
Neurodegenerative Diseases and Oncology, as well as new
therapeutic areas potentially arising out of our research and
development in Autoimmune and Inflammatory Diseases.
For more information, please visit
www.merckserono.net or www.merck.de

Target
Activity
Lipid-modifying enzymes
cPLA2
Inhibitor
Inhibitor
PLCB1, 2, 3, 4

Selective inhibitor
PI3KD
PI3K/mTOR
Dual inhibitor
LTA4 hydrolase
Inhibitor
SHIP1
Activator
SphK1, 2
Inhibitor
COX1/2
Dual inhibitor
COX2
Selective inhibitor
5-LO
Inhibitor
Autotaxin
Inhibitor
Lipid-signalling proteins
Inhibitor (ATP competitive
PKBA
binding)
Inhibitor (allosteric binding)
PKBA

5)P

Ins

b
Rhe

/
C1
TS

PKB

PI3K c

p85

Wymann, M. P. & Schneiter, R. Lipid signalling in disease.

Nature Rev. Mol. Cell Biol. 9, 162176 (2008).
This review is part of a special Focus on Lipids:
www.nature.com/nrm/focus/lipids

NH

(4,

IRS

Accompanying review

Sph

ns

G
DA

E
PT

RX

Matthias P. Wymann is at the Institute of Biochemistry and

Genetics, Department of Biomedicine, University of Basel,
Mattenstrasse 28, CH-4058 Basel, Switzerland. | Thomas Rckle is
at the Department of Operational Excellence Research and
Matthias Schwarz is at the Department of Chemistry, Merck
Serono SA, 9 Chemin des Mines, CH-1202 Geneva, Switzerland. |
Christian Rommel is at Intellikine Inc., 10931 North Torrey Pines
Road, Suite 103, La Jolla, California 92037, USA. | Roger Schneiter
is at the Division of Biochemistry, Department of Medicine,
University of Fribourg, Chemin du Muse 5, CH-1700 Fribourg,
Switzerland. | e-mails: matthias.wymann@unibas.ch;
thomas.ruckle@merckserono.net
The authors would like to thank J. F. Arrighi, T. Bohnacker,
A. Chollet, E. Collmann, D. Erhart, D. Finsinger, P. Fotiadou,
B. Franon, C. Kant, R. Marone, T. Martin, A. Melone, A. Mertz,
E. Sebille, R. Walser and M. Wuchrer for their help.
Poster design by Vicky Askew, edited by Arianne Heinrichs,
copyedited by Anne Blewett. 2008 Nature Publishing Group.

13

PLC


dI

C1

Contact information and acknowledgements

ERK

S1P

Ab

Pt

HO

AB
CC

SH2

DD

4 5

NSD

se
nSMa

S1

S1P

Ras

PPA
R

In
td

26

NucR

56 5
7
60 6 58 5
1 62 9
63

VEG

OH

COX, PLA2, 5-LO

Cer

e
nc
a
C

SphK, CerK

Cer

SMase

5-LO, 5-lipoxygenase; ALX, lipoxin A(4) receptor; C1/2 domain, conserved

region-1/2; C1P, ceramide 1-phosphate; CCR, chemokine receptor; Cer,
ceramide; CerK, ceramide kinase; COX, cyclooxygenase; cPLA2, cytosolic
phospholipase A2; DAG, diacylglycerol; DD, death domain; DP, prostaglandin D;
EP, prostaglandin E; ER, oestrogen receptor; ERK, extracellular signal-regulated
kinase; FABP4, fatty acid-binding protein-4; FcERI, high-affinity IgE receptor;
FFA, free fatty acid; FP, prostaglandin F2A; FPRL1, formyl peptide receptorlike-1; GEF, guanine-nucleotide exchange factor; GF, growth factor; Ig,
immunoglobulin; IGF, insulin growth factor; IKK, inhibitor of NF-KB; Ins, insulin;
Ins(1,4,5)P3, inositol-1,4,5-trisphosphate; IP, prostacyclin PGI2; IRS, insulin
receptor substrate; JNK, c-Jun N-terminal kinase; LPA, lysophosphatidic acid;
LT/A4/B4, leukotriene/A4/B4; LXR, liver X receptor; mTORC, mammalian target
of rapamycin complex; NSD, neutral sphingomyelinase domain; nSMase, neutral
sphingomyelinase; NucR, nuclear receptor; PDK1, phosphoinositide-dependent
kinase-1; PG, prostaglandin; PGH2S, prostaglandin H2 synthase; PH, pleckstrin
homology; PI3Kc, catalytic subunit of phosphatidylinositol 3-kinase; PKB, protein
kinase B; PKC, protein kinase C; PLA2/C/D2; phospholipase A2/C/D2;
PPAR, peroxisome proliferator-activated receptor; PtdIns(3,4,5)P3,
phosphatidylinositol-3,4,5-trisphosphate; PtdIns(4,5)P2, phosphatidylinositol-4,5bisphosphate; PTEN, phosphatase and tensin homologue; pTyr, phosphorylated
Tyr; PXR, pregnane X receptor; RAR, retinoic acid receptor; Rapa, rapamycin
(the FKBP12rapa complex functions as an mTOR inhibitor); Rheb, Ras
homologue enriched in brain; ROS, reactive oxygen species; RXR, retinoid X
receptor; S1P, sphingosine 1-phosphate; SERM, selective oestrogen receptor
modulator; SH, Src homology; SHIP1, SH2 inositol 5-phosphatase-1; SM,
sphingomyelin; Sph, sphingosine; SphK, sphingosine kinase; TG, triacylglycerol;
TLR, Toll-like receptor; TNFA, tumour necrosis factor-A; TP, thromboxane A2/
prostanoid; TSC, tuberous sclerosis; VEGF, vascular endothelial growth factor.
For simplicity, actions of extracellular lipids, such as LTs, PGs, LPA, FFA, etc.,
on nuclear receptors were omitted.

OH
N

Abbreviations

protein kinase cascades, nuclear receptors, stimulate guanine

nucleotide exchange factors and small GTPases, while others act
extracellularly on GPCRs. These signals therefore control metabolism,
growth, proliferation and cell migration. Here, we provide an overview
of this protein-lipid signalling network, and how it can be exploited to
attenuate proliferative, inflammatory and metabolic disease.

PKCB
PDK1
Lipid receptors
ER
ER

RARA
RARB
RAR
RARG
LTD4 receptor
LTB4 receptor
LXR/PXR

26
27, 28

29
30
31

TP receptor
Antagonist
Terutroban S18886
44
ALX (FPRL1,
Agonist
Cpd 43
45
CCR12)
56 Inflammation, transplant
S1P1, 3, 4, 5
Agonist
FTY720
46
receptors
rejection, cancer (Phase III)
57 (discovery)
S1P1 receptor
Selective agonist
AUY-954
47
58 (discovery)
S1P1 receptor
Selective antagonist
W146
48
59 (discovery)
S1P2 receptor
Selective antagonist
JTE-013
49
60 (discovery)
S1P3 receptor
Selective antagonist
Example 6 in PCT
50
61 (discovery)
S1P4 receptor
Agonist
Example 2 in PCT
51
62 (discovery)
S1P4/5 receptor
Dual agonist
Cpd 18
52
63 (discovery)
S1P1, 5 receptor
Dual agonist
Cpd 26
53
The above list is a representative set of small molecules directed against lipid-modifying enzymes, lipid-signalling proteins
or lipid receptors. Compounds are selected on the basis of the highest development status or greatest target selectivity.

Syk

p85

SH2 SH2

PI3Kc

6 9

5)P
Ptd
Ins(

PI3
K

GE

C

Rh
o

3,4,

Fyn

S
PLC H2


Btk

22

PGH
2

LTs

5-LO

ER

40

PPA
R

14 15

PGs

Rho

Cyto
PK
kin
C
esi
s
Proli
fer
ati
27
on
ER

mT
OR
C2

S47
3

mTORC1

25
2

28

16

PK

18 19
2

P
P

PI3K
c

S6K

OH
N

PK
K

JN

ty
tili
o
M

Inflammation



IRS

IKK

IgE
FcRI

PKC 
PKC

JNK

)P 3

SH2

SHIP1

12

AA

DA

ROS
ER stress

30

G
DA

2
PPA

TG

B
-
F
N

PPAR

,5
s(3,4

P
P

29

R
RX

8
37 3

LXR

Cer

PKB

PI3K c

p8 5

41 42

PP 9
AR


1
2
cPLA

31
3

2+
Ca

RA 4
R

2+
Ca

33
3

rK

Growth

H
O
N

Ce

p8 5

Ce
r

P t d In

2
C2
C1 KC
P

C1

Pro

esis
ynth
s
n
tei

IK

FAB
P

DD

Activation
Inhibition
Indirect action

NSD

OH

TLR4

et
F
ab
CO FA
oli O
cd
ise
Translocation
ase
Conversion

C
L
P

Cer

Cer

TNF

ran
g
De

GP

F1
/IG

st

OH

Ins

CO FFA
O

CR

K

Adenosine
Chemokines 55
Bacterial peptides
Eicosanoids
Prostanoids 43 44

ion
t
a
ul

45 46 47 48 49 50
51 52 53 54 55
Leukotrienes 35 36

Extracellular
lipid-modifying
enzymes 3 11 17
Migration of macrophages
to adipose tissue

For a list of references and an

expanded table, see:
www.nature.com/nrm/
posters/lipidsignalling-disease

Los seres humanos somos hijos del hambre

Nio de Nariokotome

Homo ergaster 1.6 mA

correspondiente a un joven homnido que

falleci entre los 11 a 12 aos de edad
hace aproximadamente 1,6 millones de
aos (inicios del Pleistoceno). El esqueleto
fue descubierto el 23 de agosto de 1984
por el experto buscador Kamoya Kimeu,
miembro del equipo de paleoantroplogos
que entonces diriga Richard Leakey.

Ante la falta de vegetales nuestros

antecesores tuvieron que recurrir a la carne

La caza y la pesca exigian un considerable

esfuerzo fsico y una gran actividad cerebral

Ingestin de
proteinas
+

Ingestin de
carbohiratos
AA

Insulina

Try/AA

Serotonina

Mecanismo de seleccin dietetica

Glucosa

ACIDOS GRASOS

Nosotros no somos herbivoros, solo podemos

comer unos vegetales raros que se llaman
hortalizas y verduras

Un 50% de nuestra alimentacin debe

ser como la del Ardipithecus Ramidus

Frutas de cualquier tipo y cuanto mas

mejor, verduras de hoja, verduras de
yema y de fruto, infloraciones, raices y
bulbos, 20 gramos de fibra. 5 comidas al
dia.

Un 30% debe ser como la del

Australopithecus Afarensis

Tuberculos, semillas verdes, frutos secos,

miel, pequeos animales, huevos, insectos
y peces

Un 18% debe ser como la del Homo

Ergaster

Carne de cualquier animal, pescados,

moluscos y crustceos, huevo y pescado

Un 2 % debe incluir las novedades

aportadas por el Homo Sapiens sapiens

Cereales refinados, legumbres, leche y su

derivados, bebidas fermentadas, dulces,
aceites, mantequilla, margarina, sal