Biologically inactive leptin and early-onset extreme obesity
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Transcript of Biologically inactive leptin and early-onset extreme obesity
María Daniela Bechara Mestra
Melissa Cano Bustamante
Medicine Students
3 semester
INTRODUCTION
Obesity is one of the most common diseases in our society. Sedentarism
and fatty diet are involved in most of cases as the etiology of this disease
and most of the times treatment is focused in these problems, but there are
some cases in which obesity appears in an early age and parents have a
normal weight. For this reason scientists have made several studies trying to
find a explanation to this, for instance genetic mutations as a etiology of
this condition. Mutations in leptin gen are involved in etiology of early onset
extreme obesity.
INTRODUCTION: LEPTIN
Leptin is a hormone that is synthesized by adipocytes in order to inform to
the brain the energy levels derived from fats, in this way, this hormone
controls oral intake and body weight.
Leptin is a 167 aminoacid protein produced by LEP gen in cromosome 7.
this protein has four alfa hélix and a disulfide bond that is needed to be
biologically active.
Leptin receptor (hLR) is located in hypotalamus cells in central nervous
sistem and it is produced by its gen (LEPR).
INTRODUCTION
OBESITY
Abnormal or excessive fat accumulation that may impair health (OMS).
A BMI greater than or equal to 30 is obesity
OBESITY
Early onset extreme obesity is a
special condition in which
children rapidly gain weight in the
posnatal period despite of normal
weight at birth.
CONGENITAL DEFICIENCY
This is a condition in which a substance is in a low concentration at birth.
It can be caused by:
Genetic: gene mutations,chromosomal mutations
Physical: radiation
Chemicals: drugs, toxic
Infectious: rubella, syphilis
Teratogenic agents: alcohol, synthetic estrogens, HIV
CONGENITAL DEFICIENCY
When this substance is partially or
totally reduced will generate
abnormal function in its target
(organ or system) and in this way
can cause disease.
EARLY ONSET EXTREME OBESITY
This is a disease that is present in children with a normal weight at bird but
has a rapid weight gain, also parents have a normal weight.
Several studies had found, congenital leptin deficiency or a biologically
inactive protein or mutant leptin receptor in cells is present in these children
with the disease.
OBJECTIVE
To study how congenital leptin
deficiency generates early onset
extreme obesity.
MATERIALES Y MÉTODOS
Características del paciente:
Primer hijo de 2 embarazos.
(padres sanos).
Peso al nacer 3680gr (normal).
Rápida ganancia de peso.
Mutación en el gen LEP.
2 años y 6 meses. IMC: 38.6 > 99.9
Hiperfagia
Recurrentes infecciones.
MATERIALES Y MÉTODOS
Secuenciación de DNA
Objetivo:
Determinar la secuencia de losnucleótidos.
2 métodos:
Desdoblamiento químico
Enzimático (DNA polimerasa).
MATERIALES Y MÉTODOS
Muestra de DNA.
Nucleótidos libres.
Enzima.
Primer.
MATERIALES Y MÉTODOS
Desdoblamiento Químico Enzimático
MATERIALES Y MÉTODOS
MATERIALES Y MÉTODOS
MATERIALES Y MÉTODOS
Análisis de Western Blot
Determina proteínas específicas
en una muestra.
Electroforesis de la muestra con
proteínas.
Transferir a membrana.
Coloración.
Incubación con anticuerpo.
Detección del anticuerpo.
Revelado.
MATERIALES Y MÉTODOS
Preparación de la muestra
MATERIALES Y MÉTODOS
Electroforesis en gel de acrilamida
MATERIALES Y MÉTODOS
Transferencia electroforética a una membrana
MATERIALES Y MÉTODOS
Hibridación del anticuerpo
MATERIALES Y MÉTODOS
Detección de las bandas
MATERIALES Y MÉTODOS
Producción y purificación de proteínas recombinantes de leptina.
Se realizó por medio de la introducción del gen de leptina normal
y mutante en el ADN de un baculovirus.
Este virus infecta células de trichoplusia ni.
La célula replica, transcribe y traduce ese ADN con el gen de
leptina, para que se produzcan ambas proteínas en gran cantidad.
finalmente son extraídas por medio de cromatografía secuencial.
MATERIALES Y MÉTODOS
Estudios en animales
La leptina obtenida se inyectó en ratones hembra de 8 semanas de edad.
A 6 ratones se les inyecto 0.2µ/gr de leptina normal y la misma dosis de
leptina (D100Y).
Las dosis fueron incrementadas a 0.6µ/gr por tres días.
se monitorizo el peso y la cantidad de comida ingerida por los ratones
el experimento fue aprobado por las autoridades locales.
RESULTADOS
RESULTADOS
RESULTADOS
DISCUSSION
Author ¿What Said? Yes - No
Fischer-Posovszky
P, et al
“The circulating leptin levels in our patient werewithin the range of levels found in other childrenwith extreme obesity not related to leptindeficiency”.7
No
Weigle DS,et al
“Leptin mutant was not functional and thus
could not mediate a satiety signal in the
central nervous system”.18
Yes
Farooqi IS
“Current clinical recommendations advise thatleptin serum concentrations be measured inchildren who have rapid weight gain in the firstmonths of life, to identify patients with congenitalleptin deficiency “.17
Yes
Wang J, et al
“Finally, treatment of the patient with metreleptinwas successful, resulting in a rapid change ineating behavior and significant weight loss.”19
Yes
CONCLUSIONS
Research about leptin should be a major priority of science since obesity
figures are on a sharp increase not only in adults but also in the children.
Create a exogenous leptin able to control satiety and hyperphagia in
people with a deficiency of it would lead to progress the development of
new treatments for obesity and overweight.
CONCLUSIONS
This study is important, because it gives new information about obesity, one
of the most common diseases in our society, specially, DNA mutations that
could explain obesity in children.
New alternatives to treat obesity, derived from discoveries in molecular
mechanisms involved in this disease could be performed in patients with
obesity that doesn’t respond to conventional drugs.
María Daniela Bechara Mestra
Melissa Cano Bustamante