Exposición Dr. Efrain Olszewer, Arequipa Perú, Congreso Ortomolecular 2015.

1.  obesidade

2.  Gen nuclear: 3200.000.000 combinacoes
 Genoma mitocondrial:50.000 combinacoe

3.  Influencia do meio ambiente dos gens
 Ppar regula mas de 300 gens
 Diminuicao de trigliceridiso por ativacao de
v162 de ppara
 Modulacao por omegas

4.  Acao de um nutriente ou grupo de nutrientes
nos gens
 Variante c677t em 5 a 30% da populacao
 Diminuicao de mthfr com aumento de
homocisteina

5.  Fibras musculares rapidas glicoliticas tipo II se
expresam no gen ACTN3 no cromosoma 11
 Fibras que respondem a cretina
 Atletas professionais

6.  GenTM6SF2 responsavel por colesterol em
niveis excepcionalmente saudaveis
 Nature Genetics 2014

7.  A genetica e obesidade se dividem em tres
grupos
 Monogenica
 Sindromica
 Não sindromica

8.  Um so gen defeituoso
 Inicio rapido
 Severo
 Muito raro

9.  1/25.000 nascimentos
 Existem 20 sindromes descritos com defeitos
discretos

10.  A mas frequente
 Meio ambiente e gens
 Efeito poligeico

11.  Avalia:
 Predisposicao a obesidade
 Predisposicao a obesidade abdominal
 Reducao do apetito]gasto energetico

12.  Item 05. Perfil de genotipagem para
Obesidade Multifatorial
 Gene Polimorfismo
 FTO 9939609
 GHRL 34911341
 LEP 7566605
 LEPR Lys109Arg
 MC4R 17782313
 POMC 1042571
 PPAR-γ 1801282
 INSIG2 7566605
 PLIN1 894160

13.  A proteína da obesidade e de massa de
gordura associada (tradução livre de Fat mass
and obesity-associated protein), também
conhecida como alpha-ketoglutarate-
dependente dioxigenase FTO é uma enzima no
qual nos seres humanos é codificada como FTO,
gene localizado no cromossoma 16
 Certas variantes do gene FTO parecem estar
correlacionados com a obesidade nos seres
humanos

14.  FTO= gen gorducho
 As mutacoes do }FTO agem como um
interruptor da atividade do IRX3
 Apesar de estarem longe, porem
geneticamente desprezivel
 Camundongos com dieta gorudurosa e sem
atividade fisica sem alteracao do IRX3
ficarom 20 a 30% mas magros que o grupo
padrao
 A expressao do IRX3 acontece em obesos

15.  Pacientes portadores de fto:
 Respondem a dieta hiperproteica
 Inibidores de enzimas amilase
 Inibidores da lipasa

16.  Ghrelin /ˈɡrɛlɪn/ is a 28-amino acid hunger-stimulating peptide
and hormone that is produced mainly by P/D1 cells lining the
fundus of the human stomach and epsilon cells of the pancreas.[1]
 Ghrelin together with obestatin is produced
from cleavage of the ghrelin/obestatin
prepropeptide (also known as the appetite-
regulating hormone or growth hormone
secretagogue or motilin-related peptide),
which in turn is encoded by the GHRL gene.
 Ghrelin levels increase before meals and decrease after meals.
 It is considered the counterpart of the hormone leptin, produced
by adipose tissue, which induces satiation when present at higher
levels.

17.  In some bariatric procedures, the level of ghrelin is
reduced in patients, thus causing satiation before it
would normally occur.[3]
 Ghrelin is a potent stimulator of growth hormone
secretion from the anterior pituitary gland.[4]
 The ghrelin receptor is a G protein-coupled receptor,
known as the growth hormone secretagogue receptor
 Ghrelin has been shown to activate the endothelial
isoform of nitric oxide synthase in a pathway that
depends on various kinases including Ak

18.  Sacietogenicos
 Colageno
 Captadores de agua
 Inibidores de NPY
 Moduladores de leptina

19.  :
This gene encodes a protein that is secreted by white adipocytes, and
which plays a major role in the regulation
of body weight.This protein, which acts through the leptin receptor,
functions as part of a signaling
 An increase in the level of LEP may act directly or indirectly on the CNS
to inhibit food intake and/or regulate energy expenditure as part of a
homeostatic mechanism to maintain constancy of the adipose mass
.
 Leptin receptors (Ob-Rs) are coded for by one human gene that
produces six different isoforms; Ob-Ra - Ob-Rf.Ob-Rs exist as
constitutive dimers at physiological expression levels.


20.  Activation of Ob-Rs mediates transcriptional regulation of
the hypothalamic melanocortin pathway and
downregulates endocannabinoid
expression.
 Leptin resistance has been proposed as a
pathophysiological mechanism of obesity. In obese
individuals, Ob-Ra (which is involved in active transport of
leptin across the blood-brain barrier)expression is
downregulated and the individual may be unresponsive to
leptin signals.
 Ob-R antagonists are of great interest in the development
of pharmacological treatments for obesity

21.  Modula NPY
 Resistencia a leptina e pcr
 Marcador de inflamacao

22.  Leptin receptor also known as LEP-R is a protein that
in humans is encoded by the LEPR gene.[1][2]
 LEP-R functions as a receptor for the fat cell-specific
hormone leptin.
 Function[
 The leptin hormone regulates adipose-tissue mass
through hypothalamus effects on fullness and energy
use
 Variations in the leptin receptor have been associated
with obesity[5][6] and with increased susceptibility to
Entamoeba histolytica infections

23.  Regular disbiose e permeabilidade intestinal
 Modular flora bacteriana

24.  Melanocortin receptor 4 is a protein that in
humans is encoded by the MC4R gene.[1][2][3]
It encodes the MC4 protein, a G-protein
coupled receptor that binds α-melanocyte
stimulating hormone (α-MSH).
 In murine models MC4 receptors have been
found to be involved in feeding behaviour,
the regulation of metabolism, sexual
behaviour, and male erectile function [4][5][6]

25.  In 1998, it was reported that MC4R mutations
were associated with inherited human obesity.
 They were found in heterozygotes, suggesting
an autosomal dominant inheritance pattern
 It has a prevalence of 1-2.5% in people with
BMIs of greater than 30, making it the most
commonly known genetic defect predisposing
people to obesity.

26.  Associado aosreceptores cannabinoides
 Receptos CB1
 Orexigeno
 Pholia magra
 rimonabant

27.  Pro-opiomelanocortin (POMC) is a precursor polypeptide with
241 amino acid residues. POMC is synthesized from the 285-
amino-acid-long polypeptide precursor pre-pro-
opiomelanocortin (pre-POMC), by the removal of a 44-amino-
acid-long signal peptide sequence during translation.
 Function[edit]
 Each of these peptides is packaged in large dense-core vesicles
that are released from the cells by exocytosis in response to
appropriate stimulation:α-MSH produced by neurons in the
arcuate nucleus has important roles in the regulation of appetite
and sexual behavior, while α-MSH secreted from the intermediate
lobe of the pituitary regulates the production of melanin.
 ACTH is a peptide hormone that regulates the secretion of
glucocorticoids from the adrenal cortex.
 β-Endorphin and [Met]enkephalin are endogenous opioid
peptides with widespread actions in the brain.

28.  Synthesis[edit]
 The POMC gene is located on chromosome 2p23.3.The POMC gene is
expressed in both the anterior and intermediate lobes of the pituitary
gland.This gene encodes a 285-amino acid polypeptide hormone
precursor that undergoes extensive, tissue-specific, post-translational
processing via cleavage by subtilisin-like enzymes known as prohormone
convertases.
 However, there are at least eight potential cleavage sites within the
polypeptide precursor and, depending on tissue type and the available
convertases, processing may yield as many as ten biologically active
peptides involved in diverse cellular functions.
 Cleavage sites consist of the sequences Arg-Lys, Lys-Arg, or Lys-Lys.
Enzymes responsible for processing of POMC peptides include
prohormone convertase 1 (PC1), prohormone convertase 2 (PC2),
carboxypeptidase E (CPE), peptidyl α-amidating monooxygenase (PAM),
N-acetyltransferase (N-AT), and prolylcarboxypeptidase (PRCP).

29.  The processing of POMC involves glycosylations, acetylations, and
extensive proteolytic cleavage at sites shown to contain regions of
basic protein sequences.
 These include several distinct melanotropins, lipotropins, and
endorphins that are contained within the adrenocorticotrophin
and β-lipotropin peptides.
 It is synthesized by:
 Corticotrope cells of the anterior pituitary gland
 Melanotrope cells of the intermediate lobe of the pituitary gland
 3,148±62 Neurons in the arcuate nucleus of the hypothalamus[1]
 Smaller populations of neurons in the dorsomedial hypothalamus
and brainstem
 Melanocytes in the skin

30.  No campo da biologia molecular, os receptores
ativados por proliferador de peroxissomo,
conhecidos como PPAR (Peroxisome proliferator-
activated receptor) são um grupo de proteínas
receptoras nucleares que funcionam como fatores de
transcrição que regulam a expressão dos genes.
 Os PPARs desempenham um papel essencial na
regulação da diferenciação celular, desenvolvimento,
e metabolismo (carboidratos, lipídios, proteínas), e
carcinogênese de organismos superiores

31.  Modulan adiponectina e resistina
 Sua inbicao ativa citocinas
 Sua inibica inativa leptina
 Modulacao nutricional e farmacologica

32.  Insulin induced gene 2, also known as INSIG2, is a
protein which in humans is encoded by the INSIG2
gene.[1][2]
 Regulation[edit]
 Insulin activates the human INSIG2 promoter in a
process mediated by phosphorylated SAP1a. [3]
 MCHR2 has been observed to significantly decrease
INSIG2. [5]
 Insig2 is upregulated under hypoxic conditions and is
associated with the malignant potential of pancreatic
cancer.[6]

33.  A novel 1alpha,25-dihydroxyvitamin D3 [1,25-
(OH)2D3] response element in the promoter
region of Insig-2 gene was identified which
specifically binds to the heterodimer of
retinoid X receptor and vitamin D receptor
(VDR) and directsVDR-mediated
transcriptional activation in a 1,25-(OH)2D3-
dependent manner. 1,25-(OH)2D3 transiently
but strongly induces Insig-2 expression in
3T3-L1 cells

34.  The effects of this polymorphism on body
mass may be restricted to those already
predisposed to at least moderate obesity as a
result of environmental factors and other
predisposing genotypes.
 Associado a resistencia a insulina e
hipertensao

35.  Uso de
 Minerais como magnesio
 Moduladores de oxido nitrico
 Moduladores de resistencia a insulina

36.  Perilipin, also known as lipid droplet-associated protein
or PLIN, is a protein that, in humans, is encoded by the
PLIN gene.[1] The perilipins are a family of proteins that
associate with the surface of lipid droplets.
Phosphorylation of perilipin is essential for the
mobilization of fats in adipose tissue.[2]
 Function[edit]
 Perilipin is a protein that coats lipid droplets in
adipocytes,[3] the fat-storing cells in adipose tissue.
Perilipin acts as a protective coating from the body’s
natural lipases, such as hormone-sensitive lipase,[4] which
break triglycerides into glycerol and free fatty acids for use
in metabolism, a process called lipolysis.[2

37.  Clinical significance[edit]
 Perilipin is an important regulator of lipid storage.[2] Perilipin
expression is elevated in obese animals and humans.
 Perilipin-null mice eat more food than wild-type mice, but gain 1/3
less fat than wild-type mice on the same diet; perilipin-null mice
are thinner, with more lean muscle mass.[6]
 Perilipin-null mice also exhibit enhanced leptin production and a
greater tendency to develop insulin resistance than wild-type
mice.
 Polymorphisms in the human perilipin (PLIN) gene have been
associated with variance in body-weight regulation and may be a
genetic influence on obesity risk in humans.[7

38.  Pacientes com stress e polimorfismo
 Pacientes com nivel elevado de stress
oxidativo e polimorfimos
 Pacientes com disbiose e marcadores
 Pacientes com deficiencia nutricionais
 Pacientes com alteracoes de desintoxicacao
hepatica