Leptin and the Regulation of the Hypothalamic–Pituitary–Adrenal Axis

Abstract

Leptin, the product of the obesity gene (ob) predominantly secreted from adipocytes, plays a major role in the negative control of feeding and acts via a specific receptor (Ob‐R), six isoforms of which are known at present. Evidence has been accumulated that leptin, like other peptides involved in the central regulation of food intake, controls the function of the hypothalamic–pituitary–adrenal (HPA) axis, acting on both its central and peripheral branches. Leptin, along with Ob‐R, is expressed in the hypothalamus and pituitary gland, where it modulates corticotropin‐releasing hormone and ACTH secretion, probably acting in an autocrine–paracrine manner. Only Ob‐R is expressed in the adrenal gland, thereby making it likely that leptin affects it by acting as a circulating hormone. Although in vitro and in vivo findings could suggest a glucocorticoid secretagogue action in the rat, the bulk of evidence indicates that leptin inhibits steroid‐hormone secretion from the adrenal cortex. In keeping with this, leptin was found to dampen the HPA axis response to many kinds of stress. In contrast, leptin enhances catecolamine release from the adrenal medulla. This observation suggests that leptin activates the sympathoadrenal axis and does not appear to agree with its above‐mentioned antistress action. Leptin and/or Ob‐R are also expressed in pituitary and adrenal tumors, but little is known about the role of this cytokine in the pathophysiology.

Introduction

Leptin (from the Greek λεπτóς, thin) is a 147‐amino acid residue peptide, first described by Zhang et al. (1994). It is the product of the obesity gene (ob) and is predominantly secreted by adipocytes and stomach (Myers 2004, Zhang 1994, Zhang 2005). Leptin plays a role in the control of feeding, acting to decrease caloric intake and to increase energy expenditure (Ahima 2000, Mantzoros 1998, Myers 2004, Remesar 1997, Unger 2000, Zhang 2005).

Compelling evidence indicates that peptides involved in the regulation of food intake (e.g., beacon, cholecystokinin, galanin, neuropeptide‐W, neuropeptide‐Y, and orexins) (Baker 2003, Bedecs 1995, Cerda‐Reverter 2000, Collier 2000, Crawley 1994, Wolf 1998) control the function of the hypothalamic–pituitary–adrenal (HPA) axis, acting on both its central and peripheral branch (Andreis 2005, Andreis 2007, Hochól 2007, Krysiak 1999, Malendowicz 1994, Malendowicz 2003b, Mazzocchi 1998, Mazzocchi 2005, Nussdorfer 2005, Rucinski 2005a, Rucinski 2005b, Spinazzi 2005, Spinazzi 2006). Accordingly, leptin also regulates neuroendocrine axes, including the HPA one (Ahima 2000, Bates 2003, Casanueva 1999, Sahu 2003, Wauters 2000).

The interactions of peptides regulating food intake, and especially leptin, with the HPA axis are of great relevance, inasmuch as glucocorticoid hormones are known to be involved in the control of energy homeostasis and adipogenesis (Jeong 2004, Mastorakos 2004). At low concentrations, glucocorticoids exert anabolic effects and stimulate feeding, adipocyte differentiation, and normal fat deposition (Campfield 1996, Dallman 1993, Freedman 1986, Hauner 1987). The permissive role of glucocorticoids in the development of obesity is suggested by experiments showing that adrenalectomy prevents the progression of obesity in genetically obese Zucker rats (Freedman et al., 1986) and high doses of glucocorticoids cause excessive fat storage (Davenport et al., 1989). On the other hand, glucocorticoids have been reported to enhance leptin expression in and secretion from adipocytes (Slieker 1996, Zakrzewska 1997), an effect that could dampen their anabolic action.

Despite the large number of investigations carried out in the past 12 years and the physiological relevance of the matter, only two short survey articles have been published on the role of leptin in the regulation of the HPA axis (Glasow 2000, Wauters 2000). Thus, after a brief account of the biology of the leptin system, we will review findings indicating that leptin and/or its receptors (R) are expressed in the anatomical components of the HPA axis and that leptin plays a role in the functional regulation of the HPA axis under both physiological and pathological conditions.