ob (db) wt obesity and leptin 2010 albert lasker award douglas coleman jeffrey m. friedman for the...

ob

(db)

WT

Obesity and Leptin

2010 Albert Lasker award

Douglas Coleman Jeffrey M. Friedman

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

瘦體素

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

ob lacks a blood-borne satiety factor (leptin)

db overproduce a blood-borne satiety factor, but un-responsive(defect in leptin receptor)(feedback regulation)

Effects of parabiosis of obese with diabetes and normal miceColeman (1973) Diabetologia 9:294-8

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

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

•reduced food intake•increased energy expenditure•weight loss.

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

Expression of ob Gene in Adipose CellsREGULATION BY INSULIN*

JBC 271:2365–2368, February 1996

Leptin binding to mouse brain slice

Choroid plexus

Expression cloning:

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

=> Binding to murine AP-OB fusion protein

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

J. Clin. Invest. 108:1113–1121 (2001)

Multiple receptor isoforms

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

Genome Res. 1995 5: 5-12

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

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

Nature 395:763-770 (1998)

Biological response to high versus low leptin levels

Pathogenesis of obesity

Regulation of leptin expression and the development of obesity

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

Therapy by leptin

Most patient are resistant to leptin treatment !

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

Mechanism of leptin signaling

Das (2010) Nutrition 26 :459–473

Ruth Harris

•Insulin secretion

•Growth hormone

•Stress

•Reproduction