Physiology

Old and Fat

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Science  09 Apr 2010:
Vol. 328, Issue 5975, pp. 141
DOI: 10.1126/science.328.5975.141-c

Adipose tissue secretes the hormone leptin, which regulates food intake and energy use. The loss of leptin signaling through its receptor can cause obesity and diabetes in mice and is associated with obesity in humans, too. The leptin receptor signals in part via three tyrosine residues that become phosphorylated after leptin binds. The effects are complex because other signaling components bind to the phosphorylated residues: One attracts the JAK2 protein kinase and STAT transcription factors, and a second (Tyr985) appears to transduce both positive and negative signals, and also inhibits the receptor itself. Tyr985 is bound by the SOCS3 protein, which inhibits the activation of STAT3, and by the protein tyrosine phosphatase SHP2, which antagonizes JAK-STAT signaling. You et al. engineered mice to block phosphorylation of Tyr985. When young, these animals were leaner than controls and showed increased responses to leptin; however, as the animals aged, the opposite was true. They ate more than controls and expended less energy. Obesity induced by a high-fat diet was also more severe in the older mutant mice than in controls. Hence, Tyr985 may be important for the normal adjustment of metabolic control as mice age.

Mol. Cell. Biol. 30, 1650 (2010).

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