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瘦體素. Obesity and Leptin. 2010 Albert Lasker award. Jeffrey M. Friedman. Douglas Coleman. WT. ob ( db ). For the discovery of leptin, a hormone that regulates appetite and body weight—a breakthrough that opened obesity research to molecular exploration.

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Ob db

瘦體素

Obesity and Leptin

2010 Albert Lasker award

Jeffrey M. Friedman

Douglas Coleman

WT

ob

(db)

For the discovery of leptin, a hormone that regulates appetite and body weight—a breakthrough that opened obesity research to molecular exploration.


Ob db

Effects of parabiosis of obese with diabetes and normal mice

Coleman (1973) Diabetologia 9:294-8

db overproduce a blood-borne satiety factor, but un-responsive

(defect in leptin receptor)

(feedback regulation)

ob lacks a blood-borne satiety factor (leptin)

Coleman (2010) Nature Med. 16:1097-1099


Ob db

Nature 372: 425-432 (December 1, 1994)


Ob db

Science 269: 543-546 (July 28, 1995)

  • reduced food intake

  • increased energy expenditure

  • weight loss.


Ob db

Proc. Natl. Acad. Sci. USA 92: 9034-9037, September 1995

Expression of ob Gene in Adipose Cells

REGULATION BY INSULIN*

JBC 271:2365–2368, February 1996


Ob db

Leptin binding to mouse brain slice

Choroid plexus

Expression cloning:

Choroid plexus => mRNA => cDNA => expression in pools

=> Binding to murine AP-OB fusion protein


Ob db

Cell, Vol. 84, 491–495, February 9, 1996


Ob db

J. Clin. Invest. 108:1113–1121 (2001)


Ob db

Multiple receptor isoforms

Ahima & Flier (2000) Annu. Rev. Physiol. 62:413–37


Ob db

Genome Res. 1995 5: 5-12


Ob db

Congenital leptin deficiency is associated with severe early-onset obesity in humans

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

We have examined two severely obese children who are members of the same highly consanguineous pedigree. Their serum leptin levels were very low despite their markedly elevated fat mass and, in both, a homozygous frame-shift mutation involving the deletion of a single guanine nucleotide in codon 133 of the gene for leptin was found.


Ob db

A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction

Clement et al (1998) Nature 392: 398-401

Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced.


Ob db

Nature 395:763-770 (1998)


Ob db

Biological response to high versus low leptin levels


Ob db

Pathogenesis of obesity


Ob db

Regulation of leptin expression and the development of obesity


Ob db

Therapy by leptin

Most patient are resistant to leptin treatment !

Farooqi and O’Rahilly (2006) Endocr. Rev. 27:710-718


Ob db

Ahima & Flier (2000) Annu. Rev. Physiol. 62:413–37


Ob db

Mechanism of leptin signaling


Ob db

Das (2010) Nutrition 26 :459–473


Ob db

Ruth Harris

  • Insulin secretion

  • Growth hormone

  • Stress

  • Reproduction


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