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1、下丘脑与食欲控制,浙江大学医学院 神经生物学系 包爱民,+ -,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. T
2、wo 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.,Leptin (Greek leptos meaning thin),a mouse unable to produc
3、e leptin thus resulting in obesity (left) and a normal mouse (right),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
4、 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.,Leptin (Greek leptos meaning thin),Pathogenesis of obesity: 3 general ways that Leptin alterations lead to obesity. a, Failure to produce leptin; b, inappropr
5、iately 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. I
6、n a subset of cases, obesity is associated with normal levels of leptin.,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 t
7、he 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
8、given the highest doses of exogenous leptin produced statistically significant weight loss.,Satiety,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 P
9、VN 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 i
10、nput 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,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 pat
11、ernal chromosome. It was first described in 1956 by Andrea Prader (1919-2001), Heinrich Willi (1900-1971), 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 r
12、egion 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
13、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: sa
14、tiety 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,Prader-(Labhart)-Willi syndrome,Hypothalamic NPY-mRNA expression is increased in
15、 prolonged illness,control: + 0.71, P 0.001,PWS: r = + 0.66, P = 0.01,200,Goldstone et al. JCEM 87;927-937, 2002,Circle: control; Cross: PWS,Duration pre-mortem duration (Days),Hypothalamic AGRP ICC Staining is Increased in Prolonged Illness,control: + 0.82, P 0.001,PWS: r = + 0.91, P = 0.01,Goldsto
16、ne et al. JCEM 87;927-937, 2002,Circle: control; Cross: PWS,Duration pre-mortem duration (Days),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). S
