Fat Rats Get Lean with Leptin

Science's STKE  20 Dec 2005:
Vol. 2005, Issue 315, pp. tw453
DOI: 10.1126/stke.3152005tw453

Treatment of lean rats with the hormone leptin causes depletion of 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 by the hormone is complicated and needs to be better understood to take advantage of its potential therapeutic benefits. Wang et al. therefore designed experiments to uncover how it is that white adipocytes are able to store triglycerides while they are secreting concentrations of leptin that, when experimentally administered to lean rats, would block adipogenesis. They identified two mechanisms by which adipocytes from rats fed on a high-fat diet (60% fat) become resistant to the actions of leptin. Within 6 days after exposure to the high-fat diet, the authors detected 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). Also, after several weeks, the abundance of mRNA encoding Lepr-b was decreased. Transgenic expression of Lepr-b in adipocytes restored sensitivity of adipocytes to leptin [as measured by phosphorylation of the transcription factor STAT3 (signal transducer and activator of transcription 3)]. These mice also remained lean. In fact, the transgenic mice on the diet containing 60% fat remained as lean as control mice on the diet containing only 4% fat. The authors conclude that a high-fat diet causes resistance to leptin signaling in adipocytes and that hypertrophy and hyperplasia that cause obesity can only occur if such a mechanism allows 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.

M.-y. Wang, L. Orci, M. Ravazzola, R. H. Unger, Fat storage in adipocytes requires inactivation of leptin's paracrine activity: Implications for treatment of human obesity. Proc. Natl. Acad. Sci. U.S.A. 102, 18011-18016 (2005). [Abstract] [Full Text]