Hypothalamic pathways linking energy balance and reproduction

Abstract

During periods of metabolic stress, animals must channel energy toward survival and away from processes such as reproduction. The reproductive axis, therefore, has the capacity to respond to changing levels of metabolic cues. The cellular and molecular mechanisms that link energy balance and reproduction, as well as the brain sites mediating this function, are still not well understood. This review focuses on the best characterized of the adiposity signals: leptin and insulin. We examine their reproductive role acting on the classic metabolic pathways of the arcuate nucleus, NPY/AgRP and POMC/CART neurons, and the newly identified kisspeptin network. In addition, other hypothalamic nuclei that may play a role in linking metabolic state and reproductive function are discussed. The nature of the interplay between these elements of the metabolic and reproductive systems presents a fascinating puzzle, whose pieces are just beginning to fall into place.gonadotropin-releasing hormone; leptin; insulin; kisspeptin SINCE ANIMALS UNDER METABOLIC STRESS must invest energy in survival first and reproduction second, the reproductive axis has the capacity to respond to changes in caloric status. Indeed, every level of the reproductive axis, the hypothalamus, pituitary gland, and gonad, has the capacity to respond to metabolic cues. In humans, anorexia, cachexia, and excessive exercise can all shut down reproductive cyclicity and the secretion of gonadal steroids that are essential for the health of many organs and tissues (28,57). On the opposite end of the spectrum, obesity and diabetes can also negatively affect fertility (74,92). The mechanisms regulating these processes are not well understood, but recent work has begun to yield new insights.While long recognized, the exact nature of the relationship between energy stores and fertility has been somewhat controversial. Work in rodent models (55) and human subjects (40, 41) gave rise to the idea that a female's fat reserves must exceed a critical threshold for ovulation to occur. However, it has now become clear that the body allocates energy based on current energy balance as opposed to the absolute amount of stored adipose tissue. Ovulation is suppressed when a mammal is in negative energy balance whether that state is caused by inadequate food intake, excessive locomotor activity, or heavy thermoregulatory costs. In the mouse, ovulation occurs whenever extant energetic conditions permit, unless the process is blocked by nonmetabolic stress, social cues, or a predictive seasonal cue such as photoperiod. Mice in the wild often continue to ovulate and become pregnant during seasons of famine despite lacking the energy reserves to carry a litter to term (12). In the human, menstrual irregularities, amenorrhea, and infertility can result from inadequate food intake to compensate for energy demands; for instance, when a severe athletic training schedule is relaxed, luteinizing hormone (LH) pulses and menstrual cycles resume without a significant increase in body fat content (2...

Expanding roles of NUCB2/nesfatin-1 in neuroendocrine regulation

“…Among those, it is well known that puberty onset and fertility are sensitive to the magnitude of body fuel (energy) reserves and under the regulation of key appetite-controlling factors, such as leptin (FernandezFernandez et al 2006, Hill et al 2008. Our recent data strongly suggest that central nesfatin-1 signaling might be involved as well in the regulation of the timing of puberty in the female rat.…”

“…Compelling experimental evidence has demonstrated that central pathways and peripheral signals responsible for body weight homeostasis commonly participate also in the control of related functions, which are gated by the metabolic state of the organism (Fernandez-Fernandez et al 2006, Hill et al 2008. Among those, it is well known that puberty onset and fertility are sensitive to the magnitude of body fuel (energy) reserves and under the regulation of key appetite-controlling factors, such as leptin (FernandezFernandez et al 2006, Hill et al 2008.…”

MRI atlas of the human hypothalamus

“…Like its near neighbor, the infundibular nucleus (also termed the arcuate nucleus of the hypothalamus), damage to the ventromedial nucleus of the hypothalamus has been linked to obesity syndromes in humans (Bray and Gallagher, 1975;Carmel, 1980;Lustig, 2002;Swaab, 2006). The infundibular nucleus plays a key role in relaying peripheral information to the metabolic and the reproductive brain (Dudas and Merchenthaler, 2006;Morton et al, 2006;Hill et al, 2008;Simpson et al, 2009). The ventromedial hypothalamus, which comprises both the ventromedial nucleus of the hypothalamus and the infundibular nucleus, might be an interesting site to target for body weight control in morbidly obese patients (Halpern et al, 2008).…”

Glutamate Microinjected in the Posterodorsal Medial Amygdala Induces Subtle Increase in the Consumption of a Three‐Choice Macronutrient Self‐Selection Diet in Male Rats

“…It participates in the interpretation of olfactory/vomeronasal information and remarkable projections leave this subnucleus via the ST to reach the hypothalamic ventromedial nucleus, the anteroventral periventricular nucleus, the preoptic area, and the ventral premammillary nucleus in the hypothalamus (Newman, 1999;Dong et al, 2001;Petrovich et al, 2001). These hypothalamic nuclei considerably affect food intake and energy balance (Hill et al, 2008). The MePD also projects to the subiculum, which would be involved in prioritizing the temporal organization of motivated behaviors .…”