瘦體素 Obesity and Leptin WT ob (db) 2010 Albert Lasker award Douglas Coleman Jeffrey M. Friedman 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.

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

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

Science 269: 543-546 (July 28, 1995) reduced food intake increased energy expenditure weight loss.

Expression of ob Gene in Adipose Cells REGULATION BY INSULIN* 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

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 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.

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.

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

Therapy by leptin Most patient are resistant to leptin treatment ! Farooqi and O’Rahilly (2006) Endocr. Rev. 27:710-718

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