Novel role of the anorexigenic peptide neuromedin U in the control of LH secretion and its regulation by gonadal hormones and photoperiod

Abstract

E, Pinilla L, Tena-Sempere M. Novel role of the anorexigenic peptide neuromedin U in the control of LH secretion and its regulation by gonadal hormones and photoperiod. Am J Physiol Endocrinol Metab 293: E1265-E1273, 2007. First published August 28, 2007; doi:10.1152/ajpendo.00425.2007.-Neuromedin U (NMU) is a widely spread neuropeptide, with predominant expression at the gastrointestinal tract and brain, putatively involved in the regulation of a diversity of biological functions, including food intake, energy balance and circadian rhythms; all closely related to reproduction. Yet, the implication of NMU in the control of the gonadotropic axis remains scarcely studied. We report herein analyses on the hypothalamic expression and function of NMU in different physiological and experimental states of the rat reproductive system. Expression of NMU mRNA at the hypothalamus was persistently detected along female postnatal development, with maximum levels in adulthood that fluctuated across the cycle and were modulated by ovarian steroids. Acute central administration of NMU evoked increases of serum LH levels in pubertal female rats, while repeated injection of NMU tended to advance vaginal opening. Likewise, central injection of NMU increased serum LH concentrations in cycling female rats, with peak responses in estrus. In contrast, NMU significantly inhibited preelevated LH secretion in gonadectomized and kisspeptin-treated rats. Finally, in noncycling females due to photoperiodic manipulation (constant light), hypothalamic NMU mRNA levels were markedly depressed, but relative LH responses to exogenous NMU were significantly augmented. All together, our present data support a predominant stimulatory role of NMU in the control of the female gonadotropic axis, which appears under the influence of developmental, hormonal, and photoperiodic cues, and might contribute to the joint regulation of energy balance, biological rhythms, and reproduction. neuromedin S; luteinizing hormone; estrous cycle; estrogen; progesterone; puberty; photoperiod; suprachiasmatic nucleus; rat NEUROMEDIN U (NMU) was originally identified in the porcine spinal cord (26), and later demonstrated as a highly conserved neuropeptide found in a diversity of species, including mammals, amphibians and birds (3). Distribution of NMU has been reported as relatively ubiquitous, with prominent expression in the gastrointestinal tract, pituitary and hypothalamus; the latter including the dorsomedial, arcuate (ARC) and suprachiasmatic (SCN) nuclei (2, 3, 15). The biological actions of NMU are conducted through interaction with two different G proteincoupled receptors: FM-3/GPR66, also known as NMU receptor type-1 (NMU1R), and FM4/TGR-1 or NMU receptor type 2 (NMU2R) (12,18,19,23,39,40). Interestingly, NMU1R and NMU2R show rather distinct patterns of distribution: NMU1R is expressed in a variety of peripheral tissues, such as intestine, testis, pancreas, uterus, lung, and kidney, whereas NMU2R is selectively detected in discrete brain areas such as the parav...

Neuromedin U: A Multifunctional Neuropeptide with Pleiotropic Roles

“…In contrast, i.c.v. administration of NmU to nonovariectomized rats, a model that more closely resembles physiological conditions, suggests a role for this peptide as a positive regulator of LH and FSH release, with an overall effect of inducing early puberty signs (105 ). This is in agreement with developmentally regulated expression of NmU, the concentrations of which decrease in rats going from puberty to mature adulthood (111 ).…”

The effects of high fat diet and estradiol on hypothalamic prepro-QRFP mRNA expression in female rats

“…Increases in the intake of HFD have been linked to an overconsumption of calories, which increases the propensity for weight gain, adiposity and subsequent risk of obesity. In rodent models, food intake fluctuates across the estrous cycle and many of the hypothalamic neuropeptides that regulate feeding behavior are influenced by estrous phase (Asarian and Geary, 2006, 2013; Eckel, 1999; Gao et al, 1997; Huang et al, 1993; Khorram et al, 1985; Leibowitz et al, 1998; Olofsson et al, 2009; Petersen et al, 1993; Santollo and Eckel, 2008a; Silva et al, 2010; Vigo et al, 2007a; Vigo et al, 2007b; Wade, 1972). The goal of the current series of experiments was to examine the effects of E2 on hypothalamic prepro-QRFP (VMH/ARC, LH), QRFP-r1 (VMH/ARC) and QRFP-r2 (LH) mRNA expression in female rats fed a HFD.…”

“…Studies investigating the effects of estrous cycle, OVX and estradiol benzoate (EB) treatment on the feeding effects of various peptides and drugs have illustrated the complex role that estradiol (E2) plays on energy homeostasis (Brown and Clegg, 2010; Eckel, 1999; Eckel et al, 2002; Eckel et al, 2005; Messina et al, 2006; Rivera and Eckel, 2005; Rivera et al, 2009; Santollo and Eckel, 2008a, b). Additionally, studies have reported effects of estrous cycle and E2 treatment on the expression of hypothalamic peptides involved in feeding behavior (Gao et al, 1997; Khorram et al, 1985; Le et al, 1991; Leibowitz et al, 1998; Olofsson et al, 2009; Petersen et al, 1993; Silva et al, 2010; Vigo et al, 2007a; Vigo et al, 2007b; Zhao et al, 2005). …”

Ovarian regulation of neuromedin U and its local actions in the ovary, mediated through neuromedin U receptor 2

“…Likewise, several studies have also reported a potential central nervous system role for NMU in regulating sexual maturation and/or gonadal functions. For example, Vigo et al reported that central administration of NMU increases the serum level of LH in rats (42). However, this is in conflict with the study by Quan et al, which showed that intracerebroventricular administration of NMU to ovariectomized rats suppresses pulsatile LH secretion under either normal feeding or fasting conditions (34).…”