Leptin and the hypothalamo-pituitary–adrenal stress axis

Leptin is a 16-kDa protein mainly produced and secreted by white adipose tissue and informing various brain centers via leptin receptor long and short forms about the amount of fat stored in the body. In this way leptin exerts a plethora of regulatory functions especially related to energy intake and metabolism, one of which is controlling the activity of the hypothalamo-pituitary–adrenal (HPA) stress axis. First, this review deals with the basic properties of leptin’s structure and signaling at the organ, cell and molecule level, from lower vertebrates to humans but with emphasis on rodents because these have been investigated in most detail. Then, attention is given to the various interactions of adipose leptin with the HPA-axis, at the levels of the hypothalamus (especially the paraventricular nucleus), the anterior lobe of the pituitary gland (action on corticotropes) and the adrenal gland, where it releases corticosteroids needed for adequate stress adaptation. Also, possible local production and autocrine and paracrine actions of leptin at the hypothalamic and pituitary levels of the HPA-axis are being considered. Finally, a schematic model is presented showing the ways peripherally and centrally produced leptin may modulate, via the HPA-axis, stress adaptation in conjunction with the control of energy homeostasis.

► We review the functioning of leptin at the organ, cell and molecule level.
► Adipose leptin acts at 3 levels of the hypothalamo-pituitary–adrenal axis.
► These levels are the paraventricular nucleus, corticotropes and adrenal gland.
► Special attention is to autocrine and paracrine actions of central leptin.
► We propose how leptin controls stress adaptation and energy metabolism.