Elsevier

Physiology & Behavior

Volume 81, Issue 2, April 2004, Pages 289-317
Physiology & Behavior

Energy balance and reproduction

https://doi.org/10.1016/j.physbeh.2004.02.007Get rights and content

Abstract

The physiological mechanisms that control energy balance are reciprocally linked to those that control reproduction, and together, these mechanisms optimize reproductive success under fluctuating metabolic conditions. Thus, it is difficult to understand the physiology of energy balance without understanding its link to reproductive success. The metabolic sensory stimuli, hormonal mediators and modulators, and central neuropeptides that control reproduction also influence energy balance. In general, those that increase ingestive behavior inhibit reproductive processes, with a few exceptions. Reproductive processes, including the hypothalamic–pituitary–gonadal (HPG) system and the mechanisms that control sex behavior are most proximally sensitive to the availability of oxidizable metabolic fuels. The role of hormones, such as insulin and leptin, are not understood, but there are two possible ways they might control food intake and reproduction. They either mediate the effects of energy metabolism on reproduction or they modulate the availability of metabolic fuels in the brain or periphery. This review examines the neural pathways from fuel detectors to the central effector system emphasizing the following points: first, metabolic stimuli can directly influence the effector systems independently from the hormones that bind to these central effector systems. For example, in some cases, excess energy storage in adipose tissue causes deficits in the pool of oxidizable fuels available for the reproductive system. Thus, in such cases, reproduction is inhibited despite a high body fat content and high plasma concentrations of hormones that are thought to stimulate reproductive processes. The deficit in fuels creates a primary sensory stimulus that is inhibitory to the reproductive system, despite high concentrations of hormones, such as insulin and leptin. Second, hormones might influence the central effector systems [including gonadotropin-releasing hormone (GnRH) secretion and sex behavior] indirectly by modulating the metabolic stimulus. Third, the critical neural circuitry involves extrahypothalamic sites, such as the caudal brain stem, and projections from the brain stem to the forebrain. Catecholamines, neuropeptide Y (NPY) and corticotropin-releasing hormone (CRH) are probably involved. Fourth, the metabolic stimuli and chemical messengers affect the motivation to engage in ingestive and sex behaviors instead of, or in addition to, affecting the ability to perform these behaviors. Finally, it is important to study these metabolic events and chemical messengers in a wider variety of species under natural or seminatural circumstances.

Introduction

The link between energy balance and reproduction follows from the central unifying principle of biology, the synthetic theory of evolution. According to this theory, the physiological mechanisms that we observe in extant populations are the result of natural selection having acted on random genetic variation in the ancestral populations. Thus, the mechanisms that control energy intake, storage and expenditure exist because these mechanisms are to some degree heritable, allowed animals to survive to reproductive maturity, and conferred a reproductive advantage. Living cells require a continuous supply of fuels for biosynthesis and metabolism, but food availability and energetic demands fluctuate in most habitats, and most organisms stop eating when they engage in other behaviors that perpetuate the species. When the digestive tract is empty, the body relies on fuels and nutrients from internal and external reservoirs (body fat and food hoards, respectively). During the early evolution of animals, the ability to store significant quantities of energy inside the body and mechanisms that inhibit ingestive behaviors must have allowed animals to engage in other activities that improved reproductive success. Mechanisms that counterbalance the energetically costly activities associated with parental care of altricial offspring are presumed to have conferred a reproductive advantage. For example, some species increase energy intake during a period of intense parental care, whereas others increase both energy intake and storage in anticipation of the birth of offspring. In many bird species, the energetic needs of the new offspring require increased foraging and eating by both parents in order for the parents to produce a sufficient supply of crop milk. In mammals, lactation and parental thermoregulatory behaviors are the most energetically costly behaviors in the female repertoire. Prior to the birth of offspring, females of some mammalian species overeat and store the excess fuel as lipids in adipose tissue, and these stored fuels are later diverted to the energetic demands of lactation. In other mammalian species, food intake remains low throughout pregnancy while food hoarding increases during pregnancy to be eaten during the energetically demanding period of lactation. Thus, the mechanisms that control energy balance are integrated with those that control reproduction (reviewed in [34], [35], [224], [264], [267]), and thus, it is difficult to understand the physiology of energy balance, and the tendency of our own species toward positive energy balance and excessive energy storage, without understanding its link to reproductive success.

The ability to monitor internal and external energy availability must be central to the link between reproduction and energy balance. This ability allows animals to prioritize their behavioral options according to fluctuations in energetic and reproductive conditions. For example, when food is plentiful and energy requirements are low, energy is available for all of the processes necessary for immediate survival, including protein biosynthesis, maintenance of ionic gradients, waste removal, thermogenesis, locomotion, foraging, ingestion and digestion. Energetic priorities are set to include long-term investments, such as growth, immune function and reproduction. Behaviors related to territorial defense, courtship, mating and parental care receive a high priority, and surplus energy is stored as lipids in adipose tissue or hoarded in the home, nest or burrow.

Metabolic signals, hormonal mediators and modulators and neuropeptides give expression to these priorities in at least two interrelated ways. First, they are permissive for the neuroendocrine events that control spermatogenesis, ovulatory cycles and fertility. Second, in many species, the same metabolic signals and chemical messengers that increase the motivation to engage in reproductive behaviors also attenuate the motivation to engage in foraging, hoarding and eating (reviewed in [224], [267]).

Conversely, when energy is scarce, the physiological mechanisms that partition energy will tend to favor those processes that ensure the survival of the individual over those processes that promote growth, longevity and reproduction. The physiological processes that promote foraging, hoarding and ingestive behavior receive priority over reproduction because reproductive processes are energetically expensive and can be delayed when the survival of the individual is in jeopardy (reviewed in [32], [33], [34], [35]). For example, during seasons when food availability is low and thermoregulatory demands are high, members of some mammalian species become gonadally regressed and sexually inactive. Even in species that breed year round, reproductive processes are inhibited when food availability is low or when increased energy demands are not met by compensatory food intake [34].

During these energetic challenges, animals are predisposed toward behaviors, such as eating, foraging and food hoarding, by a variety of metabolic sensory stimuli (e.g., decreased availability of glucose and its metabolites), peripheral hormones (e.g., low plasma concentrations of insulin and leptin) and central feeding-stimulatory circuits [e.g., circuits involving neuropeptide Y (NPY) and agouti-related protein (AgRP)]. The adaptive significance of the “feeding-stimulatory” circuits is related to survival (bringing metabolic fuels, other nutrients, water, salt and other minerals into the organism to maintain cell structure and function) insofar as survival is a prerequisite to reproductive success. More important from an evolutionary perspective, the neuropeptides that stimulate eating and foraging also enhance survival during energetic challenges by inhibiting the hypothalamic–pituitary–gonadal (HPG) system. Conversely, when food is plentiful and energy demands are low, those central circuits that inhibit eating tend to facilitate aspects of reproduction. Natural selection is expected to favor those animals that curtail foraging and eating to enhance their reproductive success (reviewed in Ref. [213]).

The timing of these alternating periods of reproductive activity and quiescence differ according to species, but as a general rule, most organisms are more predisposed toward reproduction when energy is plentiful than when energy is scarce. In some species, territoriality, aggression, courtship and mating take place year round between meals, whereas in others, reproductive activities and ingestive behavior alternate within a breeding season in which energy availability is high and energy demands are low. In still other species, the energy intake and storage season precedes the breeding season. For example, in elephant seals and emperor penguins, a period of massive food ingestion and storage is followed by a 3-month period of fasting, competition for mates and breeding [9], [80], [102]. One important exception to this rule is the infertility in certain types of obesity that are due to pathologies of energy partitioning that lead to an excess storage of energy and deficits in the availability of fuels for intracellular oxidation. In such cases, infertility and overeating are the consequences of disproportionate energy storage (reviewed by [264], [267]).

Understanding the mechanisms that link energy balance to reproductive success will have clinical and agricultural benefits. It will aid in our understanding of rising obesity and associated diseases of the cardiovascular system as well as infertility and its physical and psychological sequelae. Women at both extremes of the body weight distribution and those with diabetes are at risk for various reproductive neuroendocrine disorders [153], and these disorders are typically accompanied by low circulating levels of ovarian steroids. Thus, research in this area has relevance for understanding nutritional infertility, amenorrhea, anovulation and diminished libido associated with eating disorders, such as anorexia nervosa, dieting or with increased energy expenditure that is not offset by compensatory food intake. Low levels of ovarian steroids, especially estrogens, are associated with osteoporosis and possibly with impaired cognitive function, and therefore the appropriate design of military/athletic training and nutrition programs that optimize performance and minimize injuries requires a better understanding of sex differences in the neuroendocrine link to energy balance (reviewed in Ref. [186]). Furthermore, decreased appetite and food intake influence mortality associated with cancer, inflammatory and autoimmune diseases. In addition to its clinical relevance, this area of research is central to efforts to improve breeding and lactational performance in dairy and meat animals.

In the past 10 years, several hormones and neuropeptides have been purported to mediate the link between energy balance and reproduction. This work has been driven to a large extent by a medical/pharmaceutical approach to obesity, which emphasizes the search for a product that will bring body weight and adiposity into a hypothetical healthy and fashionable limit. In contrast, this review summarizes the same recent discoveries and integrates them with important data and theoretical concepts that have developed in physiology and behavioral neuroendocrinology over the previous 30 years. Some of these concepts include the following: (1) mechanisms that control energy balance and promote energy storage are linked to reproductive success, (2) mechanisms that control the motivation to engage in behaviors are at least partially distinct from those that control the performance of the behaviors, (3) a metabolic sensory system monitors fuel availability and acts directly on central effectors, (4) hormones can act directly on the central effectors or indirectly by changing the availability of metabolic fuels, and in turn changing the metabolic stimulus, and (5) central effectors are influenced by peripheral neural inputs to the caudal brain stem, and by detectors of metabolic fuel availability in the brain stem. In this review, energy balance and its inextricable link to reproduction are viewed within a “systems” approach, which includes the physiology and behavior of whole organisms and the habitats in which they evolved.

Section snippets

Energetic effects on the HPG system

A vast array of chemical messengers and metabolic processes are involved in maintenance of energy balance. Consistent with the idea that energy-balancing mechanisms are related to reproductive success, most of these factors also influence reproductive processes, such as the HPG system. The HPG system as it functions when females are not energetically challenged is diagramed in Fig. 1A. The master control of the HPG system lies within gonadotropin-releasing hormone (GnRH) neurons, the cell

A system for organizing the factors that control energy balance and reproduction

The list of chemical messengers and metabolic events that control food intake and reproduction has grown rapidly since the cloning of the ob (obese) gene in 1994 [284]. Section 3 will organize the factors into primary sensory stimuli (Section 3.1), hormonal mediators (Section 3.2), hormonal modulators (Section 3.3), and central effector systems (Section 3.4). In Section 3.1, primary sensory stimuli refer to extero- and interosensory signals that act on sensory detectors. Exterosensory systems

Summary and conclusions

Central neuropeptides, sensory stimuli and hormonal mediators and modulators conspire to direct attention and action toward behaviors that ensure survival under energetically challenging conditions and optimize reproductive success under energetically optimal conditions. During energetic challenges, deficits in the oxidizable fuels, changes in circulating hormone concentrations, and changes in secretion of neuropeptides all show the potential to initiate processes that (1) save energy by

Acknowledgements

I sincerely thank the editor and two anonymous referees for their insightful suggestions for improving the original manuscript. In addition, I appreciate the helpful comments of Robert Blum and Laura Szymanski in preparation of this review, and especially the thorough and careful proofreading of Carolyn Buckley on various drafts of this manuscript. This work was supported by research grant IBN0096981 from the National Science Foundation.

References (286)

  • M.A Estacio et al.

    Effect of fasting and immobilization stress on estrogen receptor immunoreactivity in the brain in ovariectomized female rats

    Brain Res.

    (1996)
  • M.I Friedman

    Control of energy intake by energy metabolism

    Am. J. Clin. Nutr.

    (1995)
  • M.I Friedman et al.

    Integrated metabolic control of food intake

    Brain Res. Bull.

    (1986)
  • M Furuta et al.

    Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats

    Biochem. Biophys. Res. Commun.

    (2001)
  • N Geary

    Effects of glucagon, insulin, amylin and CGRP on feeding

    Neuropeptides

    (1999)
  • C.J Gill et al.

    Female sexual behavior is inhibited by short- and long-term food restriction

    Physiol. Behav.

    (1997)
  • H.J Grill et al.

    The neuroanatomical axis for control of energy balance

    Front. Neuroendocrinol.

    (2002)
  • S.F Abraham et al.

    Body weight, exercise and menstrual status among ballet dancers in training

    Br. J. Obstet. Gynaecol.

    (1982)
  • I.M Abraham et al.

    Estrogen receptor β mediates rapid estrogen actions on gonadotropin-releasing hormone neurons in vivo

    J. Neurosci.

    (2003)
  • R.S Ahima et al.

    Leptin accelerates the onset of puberty in normal female mice

    J. Clin. Invest.

    (1997)
  • R.S Ahima et al.

    Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia

    Endocrinology

    (1999)
  • R.S Ahima et al.

    Role of leptin in the neuroendocrine response to fasting

    Nature

    (1996)
  • A.A Ammar et al.

    NPY-leptin: opposing effects on appetitive and consummatory ingestive behavior and sexual behavior

    Am. J. Physiol., Regul. Integr. Comp. Physiol.

    (2000)
  • S.S Anderson et al.

    The energetics of sexual success of grey seals and comparison with the costs of reproduction in other piinipeds

  • D Apter

    Leptin in puberty

    Clin. Endocrinol.

    (1997)
  • P Arias et al.

    Effect of insulin on LHRH release by perfused hypothalamic fragments

    Neuroendocrinology

    (1992)
  • J.D Armstrong et al.

    Nutritionally-induced anestrus in gilts: metabolic and endocrine changes associated with cessation and resumption of estrous cycles

    J. Anim. Sci.

    (1987)
  • M Barnasco et al.

    Ghrelin and leptin pulse discharge in fed and fasted rats

    Endocrinology

    (2002)
  • M Bamshad et al.

    CNS origins of the sympathetic nervous system outflow to brown adipose tissue

    Am. J. Physiol.

    (1999)
  • I.A Barash et al.

    Leptin is a metabolic signal to the reproductive system

    Endocrinology

    (1996)
  • G.S Barsh et al.

    Genetics of body-weight regulation

    Nature

    (2000)
  • T.J Bartness

    Food hoarding is increased by pregnancy, lactation, and food deprivation in Siberian hamsters

    Am. J. Physiol.

    (1997)
  • T.J Bartness et al.

    Effects of food deprivation and restriction, and metabolic blockers on food hoarding in Siberian hamsters

    Am. J. Physiol.

    (1994)
  • D.G Baskin et al.

    Insulin in the brain

    Annu. Rev. Physiol.

    (1987)
  • F Bauche et al.

    Inhibition in vitro of acyl-CoA dehydrogenase by 2-mercaptoacetate in rat liver mitochondria

    Biochem. J.

    (1983)
  • S.A Beak et al.

    Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line

    J. Clin. Invest.

    (1998)
  • S.J Berriman et al.

    Expression of Fos-like proteins in gonadotropin-releasing hormone neurons of Syrian hamsters: effects of estrous cycles and metabolic fuels

    Endocrinology

    (1992)
  • R.J Berry et al.

    Macquarie Island house mice: a genetical isolate on a sub-Antarctic island

    J. Zool. (Lond.)

    (1975)
  • R.M Blum et al.

    Metabolic control of food intake and estrous cycles in Syrian hamsters: II. Circulating fuels and tissue leptin

    Am. J. Physiol.

    (2003)
  • R.M Blum et al.

    Fasting-induced anestrus is associated with low, while insulin-induced anestrus is associated with high plasma leptin concentrations

    Abstr. - Soc. Neurosci.

    (2000)
  • R.M Blum et al.

    Food deprivation-induced anestrus does not require adrenal secretions in Syrian hamsters

    Soc. Behav. Neuroendocrinol. Abstr. Horm. Behav.

    (2003)
  • C Broberger et al.

    The neuropeptide Y/agouti gene-related protein (AGRP). Brain circuitry in normal, anorectic and monosodium glutamate-treated mice

    Proc. Natl. Acad. Sci. U. S. A.

    (1998)
  • C Broberger et al.

    Neuropeptide Y innervation and neuropeptide-Y-Y1 receptor-expressing neurons in the paraverntricular hypothalamic nucleus of the mouse

    Neuroendocrinology

    (1999)
  • F.H Bronson

    Food-restricted, prepubertal female rats: rapid recovery of luteinizing hormone pulsing with excess food, and full recovery of pubertal development with gonadotropin-releasing hormone

    Endocrinology

    (1986)
  • F.H Bronson

    Effect of food manipulation on the GnRH–LH–estradiol axis of young female rats

    Am. J. Physiol.

    (1988)
  • F.H Bronson

    Mammalian reproductive biology

    (1989)
  • F.H Bronson

    Puberty and energy reserves: a walk on the wild side

  • F.H Bronson et al.

    Short-term hormonal responses to food intake in peripubertal female rats

    Am. J. Physiol.

    (1990)
  • J Brown

    Effects of 2-deoxy-d-glucose on carbohydrate metabolism: review of the literature and studies in the rat

    Metabolism

    (1962)
  • J.C Bruning et al.

    Role of brain insulin receptor in control of body weight and reproduction

    Science

    (2000)
  • Cited by (420)

    • Nutrition and Sexual Development in Bulls

      2024, Veterinary Clinics of North America - Food Animal Practice
    View all citing articles on Scopus
    View full text