ERA’S JOURNAL OF MEDICAL RESEARCHVOL.3 NO.1
LEPTIN, THE MEDIATOR OF ENERGY RESERVE HAS ROLE IN FERTILITY:
Department of Physiology
Era's Lucknow Medical College and Hospital, Lucknow, Uttar Pradesh India– 226003
Address for correspondence
Leptin, an adipocytokine was discovered in 1994 as putative hormone
Dr. Nitin Pandey
involved in appetite control acting at hypothalamic level. Since its discovery
Department of Physiology
lot of work has been done over this novel molecule and in variety of
Era's Lucknow Medical College and
physiological domains. Previously it was speculated that fertility, which is the
Hospital, Lucknow–226003, India
basis of species progression has link with total body mass and energy. Leptin
568 Kha/448A Geetapalli,
which is involved both in appetite regulation and reproductive process is
Alambagh,Lucknow (U.P.) PIN–226005
thought to be have role in fertility regulation. Leptin is secreted from adipose
tissue, which is marker of energy reserve of the body. In this review the role of
leptin in regulation of fertility has been discussed.
Keyword: Leptin, Adipocytokine, Body Mass and Fertility
Leptin, the obese (ob) gene product, is synthesized and
LEPTIN AS A SIGNAL OF NUTRITIONAL
secreted exclusively by adipocytes (1). Serum leptin
STATUS LINKED TO THE REPRODUCTIVE
levels correlate with the amount of body fat in rodents and
humans (2, 3) and regulate the amount of food intake by
The amount of body fat stored is known to influence
monitoring energy reserves through interaction with
fertility, indicating a link between adipose tissue and
hypothalamic leptin receptors (4). Leptin binds to its
reproductive system (15). An interesting hypothesis is
receptors on the cell membrane and is involved in the
that leptin is a peripheral signal indicating the adequacy
activation of signal transducer and activator of
of nutritional status for reproductive function (16).
transcription–3 (STAT3), a member of the signal
Therefore it seems possible that low leptin
transducer and activator of transcription family of
concentrations indicate a status of inadequate
proteins (5). In humans at least four types of splice
nutritional stores and could prevent an unwanted
variants of OB–R messenger ribonucleic acid (mrna)
pregnancy which demands additional energy to support
encoding proteins have been identified; they differ in the
a growing fetus.
length of their cytoplasmic domains (6). Although the
It is relatively well documented that leptin's central
long form, referred to as OB–RL, has the full–length
action is mediated via hypothalamic NPY gene
variant, three types of short forms, B219.1 to B219.3, lack
expression (17). In response to energy restriction or
several sequences that are responsible for intracellular
fasting, it is proposed that NPY gene expression
signaling (6). In addition to the action on energy
increases in response to a reduction in circulating leptin
metabolism, leptin appears to influence various
levels. In support of this hypothesis, Ob–Rb is
reproductive functions. Injecting leptin into ob/obmice
coexpressed in NPY neurons in the arcuate nucleus of
that are infertile and with low levels of gonadotropin
the hypothalamus in mice (18). The increase in NPY
increases the weight of the uterus and ovaries and the
production has been postulated to decrease the
number of follicles (7), resulting in restoration of fertility
stimulatory input to downstream neural pathways that
(8). Administering leptin treatment to normal female
ultimately reach the GnRHneurons. The evidence for
mice accelerates puberty (9), and in humans higher leptin
neuroendocrine effects of leptin on GnRHrelease is
levels have been shown to relate to the earlier onset of
convincing. Increased gonadotropin secretion
menarche (10). These actions of leptin are considered to
consistently occurs as a result of leptin treatment in
be mediated mainly through brain OB–R. In contrast, the
ob/ob mice and undernourished animals, presumably
m–rnaand protein of leptin and OB–R m–rnaare also
removing the inhibition of GnRH release by NPY
expressed in peripheral reproductive tissue, including
(7, 8). Therefore, leptin communicates the size of the
granulosa cells (11, 12), cumulus cells (6, 11) of human
adipose reserve to the hypothalamus. Leptin is also
preovulatory follicles, oocytes and embryos (11), and
synthesized in the reproductive tissues and it is related
human placental trophoblasts (13, 14). These findings
suggest that leptin plays a physiological role in early
47 Leptin, the mediator of energy reserve has role in fertility: a review
to the hypothalamus–pituitary–ovary axis function.
Gonadotrophin releasing harmoneand LH pulses can
be related to leptin actions. Leptin affects directly the
function of reproductive organs via paracrine effects,
1. Zhang Y, Proenca R, Maffei M, Barone M,
and may regulate oestradiol synthesis. In addition,
Leopold L, Friedman JM.Positional cloning
oestradiol concentrations could also influence leptin
of the mouse obese gene and its human
synthesis. Leptin may be a signal of metabolic status to
homologue. Nature.1994 ;(372);425– 432
the reproductive system.
2. Maffei M, Halaas J, Ravussin E, et al. Leptin
ROLE OF LEPTIN IN IMPLANTATION
levels in human and rodent: measurement of
Leptin is a small pleiotropic peptide (16 k Da)
plasma leptin and ob RNA in obese and
composed of 146 amino acid that was previously
weight–reduced subjects. Nat Med.
supposed to be related with homeostasis of energy
and food consumption and fertility (19) . But some
3. Considine RV, Sinha MK, Heiman ML, et al.
animal studies has also supported its role in
Serum immunoreactiveleptin concentrations
implantation. As we know that embryonic
in normal–weight and obese humans. N Engl J
implantation is a crucial event in reproductive
success and is dependent on the interaction between
4. Tartaglia LA, Dembski M, Weng X, et al.
the embryo and receptive endometrium. Study
Identification and expression cloning of a
supporting this is that in 1994 (1) demonstrated I
leptin receptor, OB–R. Cell.1995;
ob/obknock out mice that deficiency in leptin
synthesis is related to obesity and sterility. The
fertility of these animals is recovered with exogenous
5. Vaisse C, Halaas JL, Horvath CM, Darnell Jr
leptin treatment and not by food restriction,
JE, Stoffel M, Friedman JM. Leptin activation
suggesting that leptin is necessary for normal
of Stat3 in the hypothalamus of wild–type and
reproductive function(8). This was further supported
ob/ob mice but not db/db mice. Nat
that leptin is crucial for implantation process in
6. Cioffi JA, Van Blerkom J, Antczak M, Shafer
There exist a considerable data with respect to
A, Wittmer S, Snodgrass HR. The expression
probable involvement of leptin in human
of leptin and its receptors in pre–ovulatory
embryonic implantation process. The expression
human follicles. Mol Hum Reprod.1997;
of the leptin receptor in human endometrium has
been described (21, 22) .
7. Barash IA, Cheung CC, Weigle DS, et
ROLE OF LEPTIN IN MALE REPRODUCTIVE
al.Leptin is a metabolic signal to the
reproductive system. Endocrinology.
ecently one animal study observed the role of
Leptin in leydig cell function and spermatogenesis.
8. Chehab FF, Lim ME, Lu R. Correction of the
Administration of subphysiological to
sterility defect in homozygous obese female
physiological doses of leptin to leptin deficient
mice by treatment with the human
obese mouse, improved Leydig cell function and
recombinant leptin. Nat Genet.1996;(12);318
9. Ahima RS, Dushay J, Flier SN, Prabakaran D,
Flier JS. Leptin accelerates the onset of
Leptin, an adipocytokine was discovred as having role
puberty in normal female mice. J Clin Invest.
in appetite control also has been found to be involved
in reproductive physiology. So from above discussion
it is evident that a sufficient body mass and energy
10. Matkovic V, Ilich JZ, Skugor M, et al. Leptin is
level in the body is directly related to fertility status.
inversely related to age at menarche in human
Leptin being involved in both appetite regulation and
females. J ClinEndocrinolMetab.1997;
male and female reproductive process is putative
mediator and link between these physiological
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