sue lysate was incubated overnight at 4°C with 50 μl of the mRNA cap analogue m 7

Summary Obesity is a major risk factor driving the global type II diabetes pandemic. Yet, the molecular factors linking obesity to disease remain to be elucidated. Gender differences are apparent in humans and also observed in murine models. Here we link these differences to expression of eukaryotic translation initiation factor 4E binding protein 1 (4E-BP1), which upon HFD becomes significantly reduced in skeletal muscle and adipose tissue of male, but not female mice. Strikingly, restoring 4E-BP1 expression in male mice protects them against HFD-induced obesity and insulin resistance. Male 4E-BP1 transgenic mice also exhibit reduced white adipose tissue accumulation, accompanied by decreased circulating levels of leptin and triglycerides. Importantly, transgenic 4E-BP1 male mice are also protected from aging-induced obesity and metabolic decline on a normal diet. These results demonstrate that 4E-BP1 is a gender-specific suppressor of obesity that regulates insulin sensitivity and energy metabolism.