Neuroanatomical Framework of the Metabolic Control of Reproduction

Abstract

A minimum amount of energy is required for basic physiological processes, such as protein biosynthesis, thermoregulation, locomotion, cardiovascular function, and digestion. However, for reproductive function and survival of the species, extra energy stores are necessary. Production of sex hormones and gametes, pubertal development, pregnancy, lactation, and parental care all require energy reserves. Thus the physiological systems that control energy homeostasis and reproductive function coevolved in mammals to support both individual health and species subsistence. In this review, we aim to gather scientific knowledge produced by laboratories around the world on the role of the brain in integrating metabolism and reproduction. We describe essential neuronal networks, highlighting key nodes and potential downstream targets. Novel animal models and genetic tools have produced substantial advances, but critical gaps remain. In times of soaring worldwide obesity and metabolic dysfunction, understanding the mechanisms by which metabolic stress alters reproductive physiology has become crucial for human health.

Novel mechanisms for the metabolic control of puberty: implications for pubertal alterations in early-onset obesity and malnutrition

“…in malnutrition or anorexia) is associated with delayed puberty, excess of body energy stores (e.g. in obesity) is commonly been linked to earlier onset of puberty (Hill & Elias 2018, Manfredi-Lozano et al 2018. Moreover, in physiological conditions, a minimum of body fat mass needs to be achieved in order to attain the reproductive capacity.…”

“…Among the metabolic cues affecting puberty onset, leptin is a paradigmatic example, which plays a fundamental role as physiological link between fat stores and pubertal timing (Ahima et al 2000, Castellano & Tena-Sempere 2016. The physiological features of leptin, including its role as major reproductive modulator, have been extensively revised elsewhere (Ahima et al 2000, Louis & Myers 2007, Castellano & Tena-Sempere 2016, Hill & Elias 2018. For the purpose of this review, it is important to stress that, as adipokine being secreted in proportion of the body fat stores, leptin operates as pleotropic neuroendocrine integrator, linking the state of body energy reserves to numerous body functions, including not only weight homeostasis but also puberty and fertility.…”

Transition Period of the Dairy Cow Revisited: II. Homeorhetic Stimulus and Ketosis With Implication for Fertility

“…Consequently, various aspects of the signal cascade from hypothalamus/pituitary, ovary, and uterus and from fetal development and (under)nutrition or metabolism have been studied and described: the dominant role of GnRH in the hypothalamus/pituitary and the release of gonadotropins (HPG axis) (Wade & Jones, 2004;Schneider, 2004;Clarke, 2014;Hill & Elias, 2018), the effects of nutrition and metabolic status on circulating hormones such as LH, FSH, estradiol, progesterone, insulin, and IGF-1 and possible effects on pre-ovulatory follicle growth and ovulation (Diskin et al, 2003, Wathes, 2012, the somatotropic axis and follicular growth (Silva et al, 2009;Lucy, 2012), the regulation of the corpus luteum (Wiltbank et al, 2012), the role of glucose for embryonic and fetal development (Lucy et al, 2014), progesterone and early pregnancy (Spencer et al, 2015), prostaglandins and maternal recognition (Arosh et al, 2016), oocyte development and stress (Roth, 2018), embryonic and early fetal loss (Diskin & Morris, 2008), the role of lipids as regulators of conceptus development (Ribeiro, 2018), and the interaction between metabolic stress and innate immunity and inflammation of the endometrium (Sheldon et al, 2017).…”

“…Corresponding glucose-sensing neurons are arrayed in the brainstem and the hypothalamus (Levin, 2006). The information regarding oxidizable fuels at the fuel detector in the hindbrain is relayed to the GnRH neurons in the forebrain (details of transmitter and neurons see Wade & Jones, 2004;Schneider, 2004;Clarke, 2014;Hill & Elias, 2018). GnRH is the driver of reproduction, is secreted in a pulsatile manner from the preoptic area of the hypothalamus into the hypophysial portal system, and regulates the synthesis and pulsatile release of LH from the anterior pituitary (Clarke, 2014).…”

Neuropeptide Control of Puberty: Beyond Kisspeptins

“…2,79 Thus, situations of persistent energy deficit, such as those seen in chronic malnutrition, anorexia, or even in individuals undergoing strenuous physical exercise, are bound to delayed puberty, whereas conditions of excess of body energy reserves, as seen in early-onset obesity, are commonly linked to advanced puberty onset. 80,81 The former is the reflection of the need to attain a threshold of body energy stores (mainly, as fat depots) to reach pubertal maturation, as initially defined by the so-called critical-fat-mass hypothesis. 82 The latter is possibly at the basis of the trends for earlier onset of puberty that has been reported worldwide, especially in girls, but eventually also in boys, in parallel with the escalation of the child obesity epidemics.…”