p70S6K and AMPK converge for weight control

The hormone leptin translates information about fat stores to changes in food intake by activating signalling pathways including AMPK and PI(3)K–Akt–mTOR–p70S6K. How these pathways are integrated to elicit the appropriate physiological response has remained unclear. Kahn and colleagues now report that leptin stimulates inhibitory p70S6K-mediated phosphorylation of α2AMPK to decrease food intake and body weight (Cell Metab. 16, 104–112; 2012).

Leptin treatment in mice promoted phosphorylation of α2AMPK at Ser 491 and concomitantly decreased AMPK signalling activity. Expression of a phosphorylation-deficient α2AMPK^S491A mutant in hypothalamic regions correlated with increased food intake and body weight. Moreover, leptin treatment, which usually results in weight loss, had no effect in mice expressing the phosphodeficient α2AMPK^S491A mutant. Treating mice with PI(3)K-pathway inhibitors, or expression of dominant-negative Akt, inhibited leptin-stimulated α2AMPK phosphorylation and increased AMPK activity. The authors next found that leptin increased p70S6K activity and, using in vitro kinase and immunoprecipitation assays, demonstrated that this kinase interacted with and phosphorylated α2AMPK on Ser 491. Conversely, expression of a dominant-negative p70S6K mutant blocked leptin-induced α2AMPK phosphorylation.

These data reveal another point of crosstalk between the mTOR and AMPK signalling pathways, and elucidate a mechanism by which leptin modulates food intake and body weight.