Leptin signalling on arcuate NPY neurones controls adiposity independent of energy balance or diet composition.

Abstract

Central action of the adipocyte hormone leptin via the neuropeptide Y (NPY) system is considered critical for energy homeostatic control. However, the precise mechanisms for this control are still not clear. To specifically investigate how leptin signalling on the NPY neurone contributes to the control of energy homeostasis, we generated an inducible adult-onset NPY neurone-specific leptin receptor (Lepr) knockout model and performed a comprehensive metabolic phenotyping study. Here, we show that the NPY neurone subpopulation that is directly responsive to leptin is not required for the inhibition of fasting-induced hyperphagia by leptin, although it is essential for the regulation of adiposity independent of changes in energy balance or diet composition. Furthermore, under obesogenic conditions such as a high-fat diet, a lack of Lepr signalling on NPY neurones results in significant increases in food intake and concomitant reductions in energy expenditure, leading to accelerated accumulation of fat mass. Collectively, these findings support the notion that Lepr-expressing NPY neurones act as the key relay point where peripheral adipose storage information is sensed, and corresponding responses are initiated to protect adipose reserves.