Metabolic Regulation of Kisspeptin - Kisspeptin Signaling in Reproductive Biology - page 354

Introduction: Reproductive Function and Energy
Balance Are Closely Linked
Reproduction is essential for the survival and perpetuation of any given species;
yet, reproductive maturation and fertility are dispensable at the individual level
and, as such, various conditions that perturb organism homeostasis frequently
result in reproductive impairment. Regulation of reproductive function is highly
sophisticated and requires complex regulatory networks, which impinge upon the
so-called hypothalamic-pituitary-gonadal (HPG) axis [ 1 , 2 ]. Among the different
regulators of this neurohormonal axis, it is well known that reproductive function
is sensitive to the magnitude of energy reserves and the modulatory actions of
diverse nutritional and metabolic factors [ 3 , 4 ]. Indeed, this close link between fat-
ness and fertility was suggested from ancient times based on intuitive knowledge,
as evidenced by the fact that fertility symbols were represented as obese female
fi gures. Nonetheless, it was not until 1960s and 1970s when this contention
acquired a scientifi c basis thanks to the pioneering work of Kennedy in rodents
and, later, Frisch in humans [ 5 - 7 ]. This combination of experimental and clinical
data set the ground for the formulation of the so-called “critical fat mass hypothe-
sis” that pointed out the need to reach a certain threshold of body (fat) mass in
order to attain complete pubertal development and an appropriate reproductive
function in adulthood. This phenomenon is especially relevant in the female, where
acquisition of suffi cient fuel stores is indispensable in order to successfully face the
signifi cant amount of energy needed for pregnancy and lactation [ 8 ]. Nonetheless,
in both sexes, reproductive maturation and function are sensitive to conditions of
metabolic stress [ 9 ]. All in all, this phenomenon illustrates the tight association,
and possibly joint control, of the neuroendocrine networks governing energy bal-
ance and reproductive function (Fig. 17.1 ) [ 3 , 4 ].
Our knowledge of the neurohormonal pathways responsible for the metabolic
control of puberty onset and gonadotropic function has considerably enlarged dur-
ing the last two decades. Among the numerous endocrine regulators involved in the
integral control of reproduction and metabolism, the adipocyte hormone, leptin,
has been recognized as an essential neuroendocrine integrator linking the magni-
tude of body fat stores and different endocrine axes, including the reproductive
system [ 3 , 4 ]. In terms of body energy homeostasis, leptin is secreted by the white
adipose tissue in proportion to the amount of body energy stores and acts as anorex-
igenic and thermogenic factor at the hypothalamic level, thus contributing to
dynamically adjust energy requirements, fat reserves, and food intake [ 8 ]. It is
worth noting that, in terms of reproductive control, leptin seems to play a key role
as permissive, rather than trigger, signal for puberty onset and fertility [ 10 , 11 ], so
that threshold leptin levels are mandatory, but not suffi cient per se, to attain a nor-
mal pubertal development and to maintain reproductive function in adulthood. Yet,
recent data suggest that leptin might not be as critical as originally thought in restoring
normal gonadotropic function during exit from negative energy balance condition
in rodents and sheep [ 12 , 13 ]; a phenomenon which is yet to be fully validated. As an