La pandemia de la obesidad

Are you Biased Against Overweight Patients?

• Fat people are good and lazy; thin people are bad and motivated

• Fat people are bad and motivated; thin people are good and lazy

• Fat people are bad and lazy; thin people are good and motivated

• Fat people are good and motivated; thin people are bad and lazy

Are you Biased ? • Anywhere from 30% to 40% of health care

providers who specialized in obesity treatment answered:

Fat people are bad and lazy; thin people are good and motivated ● Indicating bias or negative attitudes towards the

overweight and obese patient

● Much of this bias is related to a lack of knowledge

Teachman BA, Brownell KD. Int J Obes Relat Metab Disord. 2001;25(10):1525-1531.

Curso MIR SEEN 2016

• “Nuevas fronteras en el tratamiento de la obesidad”……Qué datos han llevado al diseño de nuevos fàrmacos para tratar la obesidad…..y que funcionen!!!

Potential Anti-obesity Drugs and Their Pathways Complex System with Redundancy-That’s Why It’s Hard to Lose

Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi:10.1038/clpt.2010.57 Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways 5

GENES AND FAT DEPOSITION

WHICH GENES? HOW MANY?

More than 400 genes out of 16000 are involved in fat deposition

NATURE, 2003 GENOME-WIDE RNAi ANALYSIS OF Caenorhabditis elegans FAT REGULATORY GENES. Kaveh Ashrafi et al,.

Factores que influyen en el desarrollo de la obesidad

Hypothalamic Appetite Regulation

Farooqi S. Cell Metab 2006;4:260-262

3% of subjects with severe early onset obesity had a LEPR mutation

6% children with severe obesity had a mutation in the MC4 receptor

Lessons from Monogenic Obesity Syndromes

• single genetic defects can lead to severe obesity in humans • • some may be amenable to specific therapy • • insights into mechanisms involved in the regulation of

body weight • • leptin is a potent regular of energy intake, puberty and T

cell function • • MC4R deficiency is the commonest monogenic human

obesity and protects agianst obesity-induced HTA. • • Heterogeneous nature of obesity and associated

complications

Complex interactions underlying polygenic obesity

Mutch D & Clement K, Plos Genetics 2006

Nutrition Exercise Viruses

Social Status

Food Abundance

Peer pressure

Pollution Technological Progress

Psychology

Nutrition Exercise Viruses

hormones Social Status

Food Abundance

Peer pressure

Pollution Technological Progress

Psychology Psychology

Determinants of body weight

• Obesity is a complex multi-factorial disease • Differing susceptibilities in certain ethnic

groups • Heritability of fat mass = 40 - 70% (twin

and adoption studies) • Major genetic defects in severe obesity

THE HYPOTHALAMUS The most relevant part of the CNS?

THE HYPOTHALAMUS REGULATES:

• BODY TEMPERATURE. • GROWTH • REPRODUCTION • LACTATION • WATER BALANCE • COORDINATION ANS • FOOD INTAKE. • EMOTIONAL BAHAVIOUR

BRAINSTEM

LHA LHA

DMN DMN

PVN PVN

VMN VMN

PITUITARY GLAND

CEREBRAL CORTEX

BAT WAT MUSCLE

PANCREAS

LIVER GUT

Vagal

Visceral

Leptin, Adiponectin

(ADIPOSE TISSUE)

Glucocorticoids Thyroid Hormones Gonadal Steroids

(ENDOCRINE GLANDS) Insulin

(PANCREAS)

Ghrelin, PYY, CCK

(STOMACH/GUT)

BBB

NEUROPEPTIDES AND HOMEOSTASIS.THE NEED FOR ENERGY.

-GROWTH -SEX/REPRODUCTION -LACTATION -TERMOGENESIS -STRESS WHAT DO THEY HAVE IN COMMON? ONLY POSSIBLE IF ENERGY AVAILABILITY IS ADEQUATE. HOW DO THEY KNOW THAT?

THE HYPOTHALAMUS The most relevant part of the CNS?

Regulación de la ingesta y peso corporal

Regulación de la masa corporal … pura termodinámica

Gasto energético

Ingesta

Masa normal

Ejercicio

Gasto energético Ingesta

Sobrepeso y obesidad

Ejercicio

FOOD INTAKE

Balance between orexigenic/anorexigenic signals

Programming (fetal /neonatal) and lifestyle

Food preference

Hedonic component

“the hungry brain”:homeostatic vs hedonic components

Comer para sobrevivir Comer por placer: adicción

Ingesta: comer por necesidad (Adaptación) ♦Energía para sobrevivir- (=Necesidades energéticas)

♦ Necesidades nutricionales (= Variedad) ♦ Selección de alimentos –dulce, salado,…>>ácido, amargo (= Comestible>>Venenoso)

“the hungry brain”:homeostatic vs hedonic components

Comer para sobrevivir Comer por placer: adicción

♦Algunas comidas nos hacen comer más (=Refuerzo)

♦ Y provocan asociación entre comida y recompensa (= Condicionamiento) ♦ Promueven la ingesta en ausencia de necesidad energética (= Ingesta hedónica)

Ingesta: comer por placer (Recompensa)

Y qué pasa con los “adictos” a la comida: “the hungry brain”

Limbic: The nature reward pathway

NEURONATOMIA: CONTROL HEDONICO DE LA INGESTA.

sexo comida juego drogas alcoho

Recompensas naturales o artificiales

Are you a food addict?

1. Do you think about your weight constantly ? 2. Do you eat differently in private than with other people? 3. Do you eat to escape from your feeling? 4. Do you eat when you are not hungry? 5. Have you ever stolen other people’s food? 6. Have you ever hid food to make sure you have “enough?” 7. Do you frequently feel shamed or guilty about what you have eaten? 8. Do you feel hopeless about your relationship with food?

There is an ongoing discussion whether food addiction exist. ("Eating addiction", rather than "food addiction", better captures addictive-like eating behavior. Hebebrand J, Albayrak Ö, Adan R, Antel J, Dieguez C, de Jong J, Leng G, Menzies J, Mercer JG, Murphy M, van der Plasse G, Dickson SL.Neurosci Biobehav Rev. 2014 Nov;47:295-306

“the hungry brain”:homeostatic vs hedonic components

Comer para sobrevivir Comer por placer: adicción

• Orexigenic: NPY AgRP MCH β-END (POMC) GAL DYN OX-A/OX-B Endocannabinoids Ghrelin

• Anorexigenic: Leptin PYY3-36 Amilin Oleoyl-estrone Oleylethanolamide α-MSH (POMC) CART TRH CRH

Regulation of food intake

Hypothalamic regulation of energy balance

Brain

Hypothalamus

Liver Skeletal muscle

BAT WAT Beta - cell (pancreas)

Food intake

Autonomic Nervous System

Glucose and lipid metabolism Energy expenditure

Hormonal and nutritional signals

Hypothalamic neuropeptides

Anorexigenic neuropeptides

LEPTIN

Food intake

PVH PVH

DMH DMH

VMH VMH

LHA LHAPVH PVH

DMH DMH

VMH VMH

LHA LHAMCH

AgRP NPY

OXs

CRH TRH

CART

POMC α-MSH

Orexigenic neuropeptides

GHRELIN

BRAINSTEM

LHA LHA

DMN DMN

PVN PVN

VMN VMN

PITUITARY GLAND

CEREBRAL CORTEX

BAT WAT MUSCLE

PANCREAS

LIVER GUT

Vagal

Visceral

Leptin, Adiponectin

(ADIPOSE TISSUE)

Glucocorticoids Thyroid Hormones Gonadal Steroids

(ENDOCRINE GLANDS) Insulin

(PANCREAS)

Ghrelin, PYY, CCK

(STOMACH/GUT)

BBB

ob/ ob: KO de la leptina • Hiperfagia

• Obesidad mórbida • Respuesta normal a leptina

Zhang Y, et al (1994). Nature 372: 425-432

ob/ ob

• Hiperfagia

• Obesidad

ob/ ob + leptina

• Ingesta normal

• Masa corporal normal

Leptina

Zhang Y, et al (1994). Nature 372: 425-432

32 kg; 7 años

¿Existen mutaciones del gen ob en humanos?

Leptina

42 kg; 3 años

Montague CT, et al (1997). Nature 387: 903-908

Leptin

AgRP NPY

POMC CART

- +

LEPTIN. Acts at hypothalamic level -Inhibits food intake, incresed energy expenditure, decrease body weight. -

LEPTIN. Secreted by adipose tissue. -Serum levels related to adipose mass. -MORE OBESE HIGHER LEPTIN LEVELS.

LEPTIN. Obese human subjects: leptin resistance. Leptin gene or leptin receptor gene: massive obesity. -

Hypothalamic neuropeptides

Anorexigenic neuropeptides

LEPTIN

Food intake

PVH PVH

DMH DMH

VMH VMH

LHA LHAPVH PVH

DMH DMH

VMH VMH

LHA LHAMCH

AgRP NPY

OXs

CRH TRH

CART

POMC α-MSH

Orexigenic neuropeptides

GHRELIN

In 1999, Kojima et al. isolated the endogenous ligand for the GHS receptor in rat stomach.

Peptide of 28 aminoacids with a esterification in serine-3, which is essential for the biological activity.

It was identified two other forms that is different in a glutamine in position 14, Des-Gln14-Ghrelin.

GHRELIN

GHRELIN (HUMANO) GHRELIN (HUMANO)

BODY COMPOSITION

0

5

10

15

20

25

VehicleGhrelin

**

**

**

fat m

ass (

g)

7 14 21 28 Days after pump implantation

Ghrelin administration

Ghrelin

Ghrelin agonists to reverse cachexia?

• Anamorelin for patients with cancer cachexia: an integrated analysis of two phase 2, randomised, placebo-controlled, double-blind trials (Garcia et al Lancet Oncology 2015)

• Anamorelin, a ghrelin agonist, treatment for 12 weeks had a favourable clinical response profile in patients with cancer anorexia-cachexia syndrome.

NPY

AgRP

ghrelin

Hypothalamic neuron

SIRT1

p53 AMPK pAMPK

pACC

ACC Malonyl-CoA Acetyl-CoA

MCD

Palmitoyl

FAS

CPT-1

mitochondria

β-oxidation ROS

UCP-2

cytoplasm

FOOD INTAKE

BSX pCREB

FOXO 1

Figure 6

Ghrelin’s orexigenic effect is mediated by AMPK

Andersson M et al (2004) JBC 279:12005-12008

Sakkou M et al (2007) Cell Metab 5, 450-463

Kola M et al (2008) PLoS ONE 3:e1797

López M et al (2008) Cell Metab 7:389-399

Andrews ZB et al (2008) Nature 454:846-851

Lage R et al (2010) FASEB J 24:2670-2679

Velásquez DA et al (2011) Diabetes 60:1177-1185

Ramírez S et al (2013) Diabetes 62:2329-2337

Ghrelin Signals Hunger BR LU DI

(24 hour clock)

Ghrelin Level

Adapted from Williams DL, Cummings DE. J Nutr 2005;135:1320-1325

Figure 2. Relationship between plasma ghrelin concentrations and subjective ratings of hunger. Individuals with PWS (♦, overnight fast) and controls (○, 36-h fast) were asked to rate their subjective sensation of hunger in response to the questions “How much food do you think you could eat right now?” (top) and “How hungry do you feel?” (bottom)

Published in: Angelo DelParigi et al The Journal of Clinical Endocrinology & Metabolism 2002, 87, 5461-5464.

Ghrelin antagonist in obesity?

• This clinical data clearly illustrates the therapeutic potential of AZP-531, combining insulin sensitization and weight reduction, therefore supporting further developments in type 2 diabetes and Prader-Willi syndrome” said Thierry Abribat, manager of TAB Consulting, president of Alizé Pharma SAS.

DRUG TARGETS

• Most of the drug targets failed when tested in humans....Leptin only beneficial in a subjects with mutation leptin gene.

• Ghrelin? Yet promising… • We tell patients: eat less and do exercise • Think!!!! • Nicotine? • GLP-1 and combinations… • Thyroid hormones ?

Thyroid hormones and energy balance

Hyperthyroidism induces marked alterations in energy balance

López M et al (2010). Nat Med 16: 1001-1008

Days1 3 5 7 9 11 13 15 17 19 21

Body

wei

ghtc

hang

e(g

)

0

20

40

60

80

100

120

140

160 VehicleT4VehicleT4

c

c

b c

a

bb b

c c

bb

b

b b

bb

b

cc

Food

inta

ke (g

)

Days1 3 5 7 9 11 13 15 17 19 21

20

25

30

35

40c

c

cccc

ccc

ccc

ac

c

VehicleT4VehicleT4

Leanness Hyperphagia

02040

6080

100120

140160

AgRP NPY CART POMC

mR

NA

leve

ls (%

eut

hyro

id) ** **

**

02040

6080

100120

140160

AgRP NPY CART POMC

mR

NA

leve

ls (%

eut

hyro

id) ** **

** Increased hypothalamic orexigenic signalling

EuthyroidHyperthyroidEuthyroidHyperthyroid

Thyroid hormones stimulate BAT in humans

Skarulis MC et al (2009). JCEM 95: 256–262

Without T4 With T4

Increased glucose uptake after T4 treatment

Increased BAT UCP-1 after T4 treatment

Storage (fat)

Food intake

Metabolism

Energy expenditure

Thermogenesis

Physical activity

Metabolism

Energy expenditure

HYPOTHESIS

• In hyperthyroidism there is an alteration in cellular sensors of energy availability leading to increased energy expenditure and increase food intake.

• AMPK? • mTOR?

WAT Liver

Skeletal muscle Pancreatic β cell

Heart Hypothalamus

Fatty acid oxidation

Glucose uptake

Mitochondrial biogenesis

Food intake Fatty acid oxidation

Glucose uptake

Glycolysis

AMPK

Insulin secretion

Fatty acid synthesis

Cholesterol synthesis

Gluconeogenesis

Fatty acid synthesis

Lipolysis

AMPK-Cellular Sensor

• Expressed in key hypothalamic nuclei. • Regulated by feeding and fasting. • Activation of AMPK increased feeding. • Play a key role in in hypothalamic

hypoglycaemia sensing. • Regulated by different hormones and

neurotransmitters, including ghrelin.

Hypothalamic mTOR a novel whole body energy sensor

mTOR: mammalian target of rapamycin S6K1: S6 kinase 1

Woods et al (2008). Annu.Rev.Nutr. 28: 295-311 Cota D et al (2006). Science 312: 927-930

HYPOTHESIS

• In hyperthyroidism there is an alteration in cellular sensors of energy availability leading to increased energy expenditure and increase food intake.

• AMPK? ENERGY EXPENDITURE (VMH)

• mTOR? FOOD INTAKE (ARC)

New model of central T3 actions on energy balance

López M et al (2010). Nat Med 16: 1001-1008

Thyroid gland

Energy expenditure

SNS

Hypothalamus

3V

ARC

RPa IO

Body weight Body weight

SNS

3V

ARC

T3

Complex lipids

Malonyl-CoA

Acetyl-CoA

AMPK

ACC

FAS

Ucp1 Ppargc1a

Ppargc1b Ucp3

VMH

X

X TR

β3-AR

BAT

DRUG TARGETS

• Most of the drug targets failed when tested in humans....Leptin only beneficial in a few subjects (mutation leptin gene).

• Thyroid hormones ?

• Nicotine?

• GLP-1 + Glucagon/TH/ E2….

Time (days)

60

40

20

0

80

Bod

y w

eigh

tcha

nge

(g)

1 3 5 7 9 11 13 15 17-10

##

#

***

Withdrawal

Time (days)

60

40

20

0

80

Bod

y w

eigh

tcha

nge

(g)

1 3 5 7 9 11 13 15 17-10

##

#

***

Withdrawal

10

25

1 3 5 7 9 11 13 15 17

20

30

15

Time (days)

***#

##

Food

inta

ke(g

)

Withdrawal

10

25

1 3 5 7 9 11 13 15 17

20

30

15

Time (days)

***#

##

Food

inta

ke(g

)

10

25

1 3 5 7 9 11 13 15 17

2020

3030

1515

Time (days)

***#

##

Food

inta

ke(g

)

Withdrawal

Vehicle

WithdrawalNicotineVehicleVehicle

WithdrawalNicotineWithdrawalNicotine

39 ºC

26 ºC

Vehicle Nicotine

BAT

BAT

39 ºC

26 ºC

39 ºC

26 ºC

Vehicle Nicotine

BAT

BAT

What’s about pharmacology? Nicotine

Martínez de Morentin PB et al (2012). Diabetes 61:807-817

What’s about pharmacology? Nicotine

Seoane-Collazo P et al (2014). Endocrinology 155:1679-1689

Time (days)

Foo d

i nta

ke(K

cal/ d

a y)

1 3 5 7 9 11 13 15 1740

50

60

70

80

90 Withdrawal

***##

Time (days)

Foo d

i nta

ke(K

cal/ d

a y)

1 3 5 7 9 11 13 15 1740

50

60

70

80

90

Time (days)

Foo d

i nta

ke(K

cal/ d

a y)

1 3 5 7 9 11 13 15 1740

50

60

70

80

90 WithdrawalWithdrawal

***##

Withdrawal

***###

Time (days)Body

we i

ghtc

hang

e(g

)

1 3 5 7 9 11 13 15 17

-40

-20

0

20

40

HFD vehicleHFD nicotineHFD withdrawal

WithdrawalWithdrawal

***###

Time (days)Body

we i

ghtc

hang

e(g

)

1 3 5 7 9 11 13 15 17

-40

-20

0

20

40

Time (days)Body

we i

ghtc

hang

e(g

)

1 3 5 7 9 11 13 15 17

-40

-20

0

20

40

Time (days)Body

we i

ghtc

hang

e(g

)

1 3 5 7 9 11 13 15 17

-40

-20

0

20

40

HFD vehicleHFD nicotineHFD withdrawal

HFD vehicleHFD nicotineHFD nicotineHFD withdrawalHFD withdrawal

10

0

2

4

6

8

Sta

ined

area

(%)

*

0

2

4

6

8

Sta

ined

area

(%)

*

Vehicle Nicotine

Nicotine acts at hyothalamic level

• Decrease food intake at the ARC via orexigenic/anorexigenic peptides (NPY/AgRP and POMC).

• Increase energy expenditure at the VMH through a AMPK-dependent mechanism.

• Nicotine may prevent or impaired obesity development …

• YET SMOKING IS BAD FOR YOUR HELP

DRUG TARGETS

• Most of the drug targets failed when tested in humans....Leptin only beneficial in a few subjects (mutation leptin gene).

• Thyroid hormones ?

• Nicotine?

• GLP-1 + Glucagon/TH/ E2….

Effects of Liraglutide and Orlistat on Body Weight in Nondiabetic Obese Adults

Data are mean (95% CI) for the ITT population 73 Astrup A, et al. Lancet. 2009 Nov 7;374(9701):1606-16.

GLP1-R is widely expressed in hypothalamic nuclei

GLP1-R

GLP1-R

GLP1-R

GLP1-R

GLP1-R

What’s about pharmacology? Liraglutide

Beiroa D et al (2014). Diabetes

The VMH AMPK-SNS-BAT axis: a canonical pathway

Contreras C et al (2014). Ann Med (in press)

• A novel GLUCAGON/GLP-1 AGONIST ELIMINATES OBESITY IN RODENTS.

• M.Tschop.....R.Nogueiras.....R.DiMarchi (Nat Chem Biol

Oct 2009)hem Biol. 2009 Oct;5(10):749-57.

Complementary Actions of Dual Incretin PharmacologyGLP-1R agonists act directly on pancreatic islets to enhance insulin production and secretion, and in neuronal circuitries to reduce food intake. ...

Brian Finan, Timo D. Müller, Christoffer Clemmensen, Diego Perez-Tilve, Richard D. DiMarchi, Matthias H. Tschöp

Trends Mol Med 2016

Effect of long‐term liraglutide and RM‐493, a MC4-R agonist, co‐treatment on obesity and glucose metabolism in DIO mice A–F22 days of treatment of DIO male mice .

Christoffer Clemmensen et al. EMBO Mol Med. 2015;7:288-298

©2015 by European Molecular Biology Organization

Unimolecular triagonism maximizes metabolic

benefits compared with dual incretin coagonism. • A chimera with high affinitty binding to

receptors for: GLP-1 , GIP and glucagon. • More powerful than co-agonist. • (Finan B et al Nat Medcine 2015)

Potential Anti-obesity Drugs and Their Pathways Complex System with Redundancy-That’s Why It’s Hard to Lose

Valentino MA, Lin JE, Waldman SA. Clin Pharm & Therapeutics (2010) 87 6, 652–662. doi:10.1038/clpt.2010.57 Endogenous Signaling of Appetite-regulating Hormones, Neuropeptides, and Neurotransmitters, and The Drugs That Target These Pathways 86

Funded by:

Diego Pérez-Tilve Paul Pfluger

Matthias Tschöp

Rosangela Deoliveira Asish Saha

Clara Álvarez Pablo Blanco

Luz Casas Rosalía Gallego Marta Garrido Ruth González Ricardo Lage Luís Martins

Susana Sangiao Sulay Tovar Luis Varela

María J. Vázquez Douglas Velásquez

Amparo Romero Sulay Tovar

Miguel López Ruben Nogueiras

Margaret Blount Mark Campbell Janice Carter Chris Lelliott Gema Medina

Sergio Rodríguez Sam Virtue

Andy Whittle

Antonio Vidal-Puig

David Carling

Consortiums:

University of Geneva Chrystelle Veyrax-Duberaux Françoise Rohner-Jeanrenaud

UT Southwestern, Dallas Joel K. Elmquist

Beth Israel Medical Center, Boston Bradford B. Lowell

University of Iowa Kamal Rhamouni Donald A. Morgan

German Institute of Human Nutrition Potsdam-Rehbruecke Hans-Georg Joost Annette Schurmmann

Consortiums: