Transcript Leptin

下丘脑与食欲控制
浙江大学医学院 神经生物学系
包爱民
+
-
Leptin (Greek leptos meaning thin)
One of the most important adipose
derived protein hormone, 16 kDa,
regulating energy intake and expenditure,
including appetite and metabolism.
The Ob(Lep) gene is located on
chromosome 7 in human.
Mutant obese mice (1950): massively
obese and excessively voracious.
Two classes: ‘ob/ob’ - mutations in the
gene for leptin, and ‘db/db’ - mutations in
the gene that encodes the receptor for
leptin.
When ob/ob mice are treated with of leptin
(injection), they lose the excess fat and
return to normal body weight.
a mouse unable to produce leptin thus
resulting in obesity (left) and a normal
mouse (right)
Leptin (Greek leptos meaning thin)
Leptin: discovered in 1994 by Jeffrey M. Friedman et al, Rockefeller
University.
Leptin acts in the hypothalamus inhibiting appetite by
(1) counteracting the effects of neuropeptide Y;
(2) counteracting the effects of anandamide (a potent feeding stimulant,一
种内源性大麻素， “极乐酰胺”)
(3) promoting the synthesis of alpha-MSH (an appetite suppressant). This
inhibition is long-term.
Pathogenesis of obesity: 3 general ways that Leptin alterations lead to obesity.
a, Failure to produce leptin; b, inappropriately low leptin secretion for a given fat mass,
in which the fat mass would expand until ‘normal’ leptin levels are reached, c, relative
or absolute insensitivity to leptin, associated with increased circulating leptin.
In general, high plasma leptin levels are evident in obese rodents and humans. In a
subset of cases, obesity is associated with normal levels of leptin.
Satiety
Leptin binds to NPY neurons in the ARC and decreases NPY activity.
Leptin signals to the brain that the body has had enough to eat, producing
a feeling of satiety.
A very small group of humans possess homozygous mutations for the
leptin gene
a constant desire for food,
severe obesity,
treated somewhat successfully by recombinant human leptin.
However, extensive clinical trials using recombinant human leptin as a
therapeutic agent for treating obesity in humans have been inconclusive only the most obese subjects who were given the highest doses of
exogenous leptin produced statistically significant weight loss.
Model for regulation of the hindbrain response to satiety signals
Adiposity signals such as leptin acts on hypothalamic ARC neurons that project to
hypothalamic areas such as the LHA (not shown) and PVN
In turn, these ‘second order’ neurons project to hindbrain autonomic centers such as
the NTS （孤束核，一般内脏感觉神经纤维和味觉纤维终止核）that process afferent input
from satiety signals such as CCK (缩胆囊素).
Input from descending, leptin-sensitive hypothalamic projections is integrated in the
NTS with vagally mediated input from CCK, such that the timing of meal termination is
regulated by changes in body fat content.
POMC: 阿黑皮素原
FISH:Deletion 15q11-13
Prader-(Labhart)-Willi syndrome
a rare genetic disorder in which 7 genes (or some subset thereof) on chromosome
15 (q 11-13) are deleted or unexpressed (chromosome 15q partial deletion) on the
paternal chromosome.
It was first described in 1956 by Andrea Prader (1919-2001), Heinrich Willi (19001971), Alexis Labhart (1916), Andrew Ziegler, and Guido Fanconi of Switzerland.
Prader-(Labhart)-Willi syndrome
The incidence：1 in 25,000 and 1 in 10,000 live births.
The paternal origin; particular region of ch.15 involved;
parent of origin imprinting, i.e. for a number of genes
in this region only one copy of the gene is expressed
while the other is silenced through imprinting.
Parent-specific gene activation is caused by a
phenomenon called genomic imprinting
For the genes affected in PWS it is the paternal copy
that is usually expressed, while the maternal copy is
silenced: PWS people have no working copy.
Prader-(Labhart)-Willi syndrome
Hypothalamic symptoms:
• hypogonadism, underdevelopment
of the sexual organs (LHRH)
• decreased sexual behaviour
• insufficient growth (GH)
• obesity (OXT: satiety neurons)
• abnormal regulation of sleep (SCN)
• abnormal presentation of the fetus at birth, high
proportion premature or postmature births, difficult
labour (CRH, OXT)
• fits of temper, depression and sudden aggression
NPY mRNA expression (arbitrary units)
Hypothalamic NPY-mRNA expression
is increased in prolonged illness
Circle: control;
200
Cross: PWS
100
control: + 0.71, P < 0.001
10
1
PWS: r = + 0.66, P = 0.01
0.1
0.1
1
10
100
Durationpre-mortem
pre-morbidduration
illness (days)
Duration
(Days)
Goldstone et al. JCEM 87;927-937, 2002
AGRP ICC masking volume (mm 3)
Hypothalamic AGRP ICC Staining is Increased in Prolonged Illness
1
Circle: control;
control: + 0.82, P < 0.001
Cross: PWS
0.1
0.01
PWS: r = + 0.91, P = 0.01
0.001
0.1
1
10
100
Durationpre-mortem
pre-morbid illness
(days)
Duration
duration
(Days)
Goldstone et al. JCEM 87;927-937, 2002
CONTR
PVN
PWS
PVN
OXT ICC
Number of OXT-expressing (left panel) and AVP-expressing (right panel) neurons in the
PVN of 27 controls and 5 PWS patients. The values of the PWS patients are delineated by a
minimum convex polygon. Note that the OXT neurons of these patients is clearly lower than that
of the controls (left panel), which is not the case for AVP (right panel). Swaab et al. J. Clin.
Endocrin. Metab. 1995, 80:573-579.
Anorexia nervosa
an eating disorder characterized by refusal
to maintain a healthy body weight and an
obsessive fear of gaining weight.
often coupled with a distorted self image
which may be maintained by various
cognitive biases that alter how the patient
evaluates and thinks about her or his body,
food and eating.
Patients continue to feel hunger, but deny
themselves all but very small quantities of
food.
It is a serious mental illness with a high
incidence of comorbidity and the highest
mortality rate of any psychiatric disorder.
Anorexia most often has its onset in
adolescence and is most prevalent
among adolescent girls.
Can affect men and women of any age,
race, and socioeconomic and cultural
background.
The term anorexia nervosa was
established in 1873 by Sir William Gull,
one of Queen Victoria's personal
physicians.
The term is of Greek origin: an- (ἀν-,
prefix denoting negation) and orexis
(ὄρεξις, "appetite"), thus meaning a
lack of desire to eat.
"Miss A—” pictured in 1866 and in 1870 after treatment.
She was one of the earliest Anorexia nervosa case studies.
From the published medical papers of Sir William Gull.
Blouin et al.(1992) Am.J.Psych.149,
73-81