Endocrine Abstracts

The hormone leptin is required for the energy balance regulation. However, leptin also controls many other biological functions. Among these actions, some authors suggest that leptin exhibits neurotrophic effects in early life and plays a key role in the development of neurocircuitries that regulate energy metabolism. However, the precise role of leptin during development is still unclear. Thus, our study had the objective to investigate the consequences of the absence of leptin signaling during development. For this purpose, a LoxP-flanked transcription-blocking cassette was inserted in the Lepr gene to generate mice Null for the leptin receptor (LepR). This mouse was bred with animals expressing Cre-ERT2 fusion protein under the human ubiquitin C promoter sequence. Consequently, tamoxifen injections can induce Cre Recombinase activity and restore LepR gene expression in LepRNull-Ubi mice. Adult LepRNull and LepRNull-Ubi mice were morbidly obese and hyperphagic, as expected. LepR reactivation in 10 week old animals caused a robust decrease in food intake and body weight only in LepRNull-Ubi mice. While LepRNull mice remained unresponsive to leptin, an acute leptin injection was able to induce STAT3 phosphorylation in the hypothalamus of LepRNull-Ubi mice after tamoxifen treatment and reduce their food intake to a similar extent than control lean (Ubi) mice. Six weeks after LepR reactivation, food intake of LepRNull-Ubi mice was completely normalized. However, LepRNull-Ubi mice remained heavier and had higher body adiposity and leptinemia than Ubi mice, possibly due to a partial recovery in their energy expenditure. This defect is not explained by weight loss since LepR reactivation before the onset of obesity (4 weeks of life) could not prevent the suppressed energy expenditure of LepRNull-Ubi mice. In contrast, the insulin resistance exhibited by the reactivation of LepR in adult mice was no longer apparent when the reactivation occurred in younger LepRNull-Ubi mice, suggesting a weight loss-induced effect. Hypothalamic mRNA levels of AgRP and NPY were restored in LepRNull-Ubi mice, but POMC and CART expression remained suppressed. Notably, LepR reactivation in adult animals increased brain mass, but was not enough to normalize it. Conversely, the neural projections from the arcuate nucleus (ARH) to the paraventricular nucleus were completely restored in adult LepRNull-Ubi mice to levels found in lean control mice. In summary, we provided novel and substantial evidence that leptin signaling during early life is required for the energy homeostasis in adulthood, but not via the development of ARH neural projections.