This Week: Getting Lean with Leptin

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Science  06 Jan 2006:
Vol. 311, Issue 5757, pp. 17
DOI: 10.1126/science.311.5757.17b

Treatment of lean rats with the hormone leptin depleted fat from adipocytes, which of course has raised considerable interest in the possibility of using leptin as a treatment for obesity. However, failure of the hormone to reverse obesity has shown that metabolic regulation needs to be understood better in order to take advantage of its potential therapeutic benefits. Wang et al. therefore designed experiments to uncover how white adipocytes are able to store triglycerides at the same time as they secrete leptin at concentrations that, when experimentally administered to lean rats, would block adipogenesis. They identified two mechanisms by which adipocytes from rats fed a 60% fat diet become resistant to leptin. Within 6 days after exposure to the high-fat diet, there was a large increase in the expression of mRNA encoding SOCS3 (suppressor of cytokine signaling 3), an inhibitor of leptin signaling through its receptor (Lepr-b); after several weeks, the level of mRNA encoding Lepr-b decreased. The authors conclude that a high-fat diet causes resistance to leptin signaling in adipocytes and that the hypertrophy and hyperplasia that cause obesity can only occur if such mechanisms allow the adipocytes to ignore the extracellular leptin concentrations to which they are exposed. They further speculate that a period of starvation of patients might reduce such a blockade and allow a beneficial response to leptin therapy in obese patients. — NRG

Proc. Natl. Acad. Sci. U.S.A. 102, 18011 (2005).

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