Leptin is an adipocyte-derived hormone which stimulates β-oxidation in peripheral tissues and prevents steatosis. Because leptin production naturally increases during adult life, we have hypothesized that leptin receptors might undergo a physiological and gradual desensitization during ageing. Therefore we have characterized in three- five- and ten-month old mice i) the weight of different white adipose pads, heart and liver, ii) lipid content in these tissues/organs, and iii) responsiveness to acute leptin, measured in terms of phosphorylation of signal transducer and activator of transcription 3 (STAT3) and protein kinase B (Akt). In this study we have detected that leptin-mediated STAT3 phosphorylation appears to be preserved in cardiac tissue even in 10-month old animals but not in adipose tissue and liver of five- and ten-month old mice, respectively. Nevertheless, leptin increased pAkt content in the liver of these mice. In a parallel study we have analyzed the functionality of leptin signalling pathways in 10-month old obese mice and we have observed that the STAT3 pathway appears to be only operative in the heart whereas the Akt pathway remains functional both in heart and liver. Nevertheless, hepatic lipids increased almost 300% compared to age-matched lean controls. Our data demonstrate that during adult life there is a lost of leptin receptor functionality which is tissue-dependent and mainly affects the STAT3 pathway. Otherwise we demonstrate that the antisteatotic effect of leptin is independent of the Akt signalling pathway.