Leptin Indirectly Affects Estrous Cycles by Increasing Metabolic Fuel Oxidation

doi:10.1006/hbeh.1998.1453

Hormones and Behavior

Volume 33, Issue 3, June 1998, Pages 217-228

https://doi.org/10.1006/hbeh.1998.1453 Get rights and content

Abstract

In previous experiments, lean Syrian hamsters fasted on days 1 and 2 of the estrous cycle failed to show sex behavior and ovulation normally expected to occur on the evening of day 4. The first goal of the present experiment was to determine whether systemic treatment with theob(obese) protein leptin could reverse the effects of fasting on estrous cyclicity, social behaviors, and ovulation rate. Fasting-induced anestrus was reversed and normal sex and social behavior and ovulation rate were restored in hamsters injected intraperitoneally with 5 mg/kg leptin every 12 h during fasting on days 1 and 2 of the estrous cycle. A second goal was to test whether the effects of leptin could be prevented by treatment with pharmacological agents that block the oxidation of metabolic fuels. Glucose oxidation was blocked by treatment with 2-deoxy-d-glucose (2DG) and fatty acid oxidation was blocked by treatment with methyl palmoxirate (MP). 2DG (1000 mg/kg) or MP (20 mg/kg) was administered at doses that did not induce anestrus in hamsters fedad libitum.As in the first experiment, fasting-induced anestrus was reversed by leptin treatment. However, when each injection of leptin was preceded by an injection of 2DG or MP, leptin treatment did not reverse fasting-induced anestrus. In summary, estrous cyclicity was not restored when oxidation of metabolic fuels was blocked, despite high endogenous levels of leptin. These results are consistent with the hypothesis that leptin acts indirectly on the reproductive system by increasing fuel oxidation.

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It is possible that leptin's ability to exert its effects [e.g., promote reproduction, increase body temperature and metabolic rate (e.g., Mistry et al., 1997; Niewiarowski et al., 2000)] depends on its ability to mobilize energy substrates. Indeed, when administered in conjunction with treatment that blocks the oxidization of metabolic fuels, leptin cannot reverse fasting-induced anestrus in Syrian hamsters (Schneider et al., 1998). To further explore how leptin interacts with energy metabolism to influence reproduction, we aimed to determine the influence of leptin on reproductive behavior in a species that is aphagic prior to and during the mating season.
Despite the established dichotomy between investment in either reproduction or self-maintenance, a hormonal mechanism that influences an organism's decision to prioritize these behaviors remains elusive. The protein hormone leptin is a likely candidate because it is secreted from adipocytes in proportion to the amount of stored fat in numerous species. Although the majority of studies suggest that leptin stimulates reproduction, the actions of leptin can be context-dependent. Leptin increases sexual behavior in fed individuals, but inhibits sexual behavior in food-restricted individuals. We investigated if exogenous leptin influences sexual behavior in red-sided garter snakes (Thamnophis sirtalis parietalis) experiencing a predictable bout of aphagia during the mating season. We tested two doses of recombinant murine leptin injected for three days. Males were subjected to three mating trials, one on each day of injections, while females were subjected to one mating trial on the last day of injections. Leptin affects male and female snakes similarly by increasing both appetitive (i.e., mating behavior score) and consummatory (i.e., number of copulations, proportion of individuals copulated) sex behavior. We found no evidence to suggest that leptin influenced latency to copulate or duration of copulation. Because leptin promotes reproductive behavior in non-feeding garter snakes, these findings do not align with research on food-restricted mammals. Further investigations into how leptin affects sexual behavior in snakes exposed to food-restriction manipulations would clarify if the role of leptin is evolutionarily divergent.
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Leptin is a peptide hormone that is released from white adipose cells, and is a critical signal in body mass homeostasis as well as an array of reproductive functions in both sexes such as the onset of puberty and maintenance of fertility (Cheung et al., 1997; Ahima and Flier, 2000; Fernandez-Fernandez et al., 2006; Quennell et al., 2009; Hausman et al., 2012; Landry et al., 2013; Chehab, 2014; De Bond and Smith, 2014; Pankov, 2015; Perez-Perez et al., 2015). Leptin-deficient animals exhibit infertility associated with a lack of GnRH and LH pulsatile release, delayed puberty, and impaired cycling and ovulation in females, all of which are alleviated through treatment with exogenous leptin (Barash et al., 1996; Chehab et al., 1996; Mounzih et al., 1997; Schneider et al., 1998; Hill et al., 2008; Evans and Anderson, 2012; Luo et al., 2016). Seasonally breeding animals, in addition to modifying reproductive function, exhibit seasonal changes in a host of physiological parameters, such as body mass, food intake, and immune function (reviewed in Bartness and Wade, 1985; Nelson et al., 2002).
Animals living in temperate climates respond to environmental cues that signal current and future resource availability to ensure that energy resources are available to support reproduction. Siberian hamsters (Phodopus sungorus) undergo robust gonadal regression in short, winter-like photoperiods as well as in response to mild food restriction in intermediate photoperiods. The goal of the present study was to investigate whether leptin is a relevant metabolic signal in regulating gonadal regression in response to diminishing food availability. Adult female hamsters housed in short-day (winter-like) or intermediate (fall-like) photoperiods received either ad libitum access to food or mild food restriction (90% of ad libitum intake) and were treated with either leptin or a vehicle for five weeks in order to determine the ability of leptin to inhibit gonadal regression. At the end of five weeks, vehicle-treated hamsters showed physiological signs associated with ongoing gonadal regression, such as decreases in body mass and food intake, cessation of estrous cycling, and small decreases in reproductive tissue mass. Leptin did not modify changes in body mass, food intake, hormone concentration, or tissue mass, but showed a tendency to support estrous cycling, particularly in response to food restriction in the intermediate photoperiod treatment. Overall, leptin appears to play a minor role in coordinating reproductive responses to multiple environmental cues, at least in the early stages of gonadal regression.
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Most free-living animals have finite energy stores that they must allocate to different physiological and behavioral processes. In times of energetic stress, trade-offs in energy allocation among these processes may occur. The manifestation of trade-offs may depend on the source (e.g., glucose, lipids) and severity of energy limitation. In this study, we investigated energetic trade-offs between the reproductive and immune systems by experimentally limiting energy availability to female Siberian hamsters (Phodopus sungorus) with 2-deoxy-d-glucose, a compound that disrupts cellular utilization of glucose. We observed how glucoprivation at two levels of severity affected allocation to reproduction and immunity. Additionally, we treated a subset of these hamsters with leptin, an adipose hormone that provides a direct signal of available fat stores, in order to determine how increasing this signal of fat stores influences glucoprivation-induced trade-offs. We observed trade-offs between the reproductive and immune systems and that these trade-offs depended on the severity of energy limitation and exogenous leptin signaling. The majority of the animals experiencing mild glucoprivation entered anestrus, whereas leptin treatment restored estrous cycling in these animals. Surprisingly, virtually all animals experiencing more severe glucoprivation maintained normal estrous cycling throughout the experiment; however, exogenous leptin resulted in lower antibody production in this group. These data suggest that variation in these trade-offs may be mediated by shifts between glucose and fatty acid utilization. Collectively, the results of the present study highlight the context-dependent nature of these trade-offs, as trade-offs induced by the same metabolic stressor can manifest differently depending on its intensity.
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The neuroendocrinology of ingestive behavior is a topic central to human health, particularly in light of the prevalence of obesity, eating disorders, and diabetes. The study of food intake in laboratory rats and mice has yielded some useful hypotheses, but there are still many gaps in our knowledge. Ingestive behavior is more complex than the consummatory act of eating, and decisions about when and how much to eat usually take place in the context of potential mating partners, competitors, predators, and environmental fluctuations that are not present in the laboratory. We emphasize appetitive behaviors, actions that bring animals in contact with a goal object, precede consummatory behaviors, and provide a window into motivation. Appetitive ingestive behaviors are under the control of neural circuits and neuropeptide systems that control appetitive sex behaviors and differ from those that control consummatory ingestive behaviors. Decreases in the availability of oxidizable metabolic fuels enhance the stimulatory effects of peripheral hormones on appetitive ingestive behavior and the inhibitory effects on appetitive sex behavior, putting a new twist on the notion of leptin, insulin, and ghrelin “resistance.” The ratio of hormone concentrations to the availability of oxidizable metabolic fuels may generate a critical signal that schedules conflicting behaviors, e.g., mate searching vs. foraging, food hoarding vs. courtship, and fat accumulation vs. parental care. In species representing every vertebrate taxa and even in some invertebrates, many putative “satiety” or “hunger” hormones function to schedule ingestive behavior in order to optimize reproductive success in environments where energy availability fluctuates.
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^☆: J. D. FernstromG. D. Miller

¹: To whom correspondence should be addressed at Department of Biological Sciences, Lehigh University, 111 Research Drive, Bethlehem, PA 18015. Fax: (610)758-4004. E-mail:[email protected].

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Regular ArticleLeptin Indirectly Affects Estrous Cycles by Increasing Metabolic Fuel Oxidation☆

Abstract

Role of leptin in the neuroendocrine response to fasting

Nature

Leptin accelerates the onset of puberty in normal female mice

J. Clin. Invest.

Leptin in puberty

Clin. Endocrinol.

Obese gene expression alters the ability of 30A5 preadipocytes to respond to lipogenic hormones

J. Biol. Chem.

Leptin is a metabolic signal to the reproductive system

Endocrinology

Effects of 2-deoxy-d

Metabolism

Involvement of the gastric vagal nerve in the suppression of pulsatile luteinizing hormone release during acute fasting in rats

Endocrinology

Recombinant mouse ob protein: Evidence for a peripheral signal linking adiposity and central neural networks

Science

The ob protein (leptin) pathway—A link between adipose tissue mass and central neural networks

Horm. Metab. Res.

Leptin receptors in the adrenal medulla of the rat

Am. J. Physiol.

Influence of endogenous leptin tone on the estrous cycle and luteinizing hormone pulsatility in female rats

Neuroendocrinology

Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin

Nat. Genet.

Correction of the sterility defect in homozygous obese female mice by treatment with the human recombinant leptin

Nat. Genet.

Early onset of reproductive function in normal female mice treated with leptin

Science

Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy

Proc. Natl. Acad. Sci. USA

Evidence that the diabetes gene encodes the leptin receptor: Identification of a mutation in the leptin receptor gene indb/db

Cell

Leptin is a metabolic gate for the onset of puberty in the female rat

Endocrinology

Phenotypes of mousediabetesfatty

Science

Novel B219/OB receptor isoforms: Possible role of leptin in hematopoiesis and reproduction

Nat. Med.

Expression of the functional leptin receptor mRNA in pancreatic islets and direct inhibitory action of leptin on insulin secretion

Diabetes

Anatomic localization of alternatively spliced leptin receptors (Ob-R) in mouse brain and other tissues

Proc. Natl. Acad. Sci. USA

Leptin expression and action: New experimental paradigm

Proc. Natl. Acad. Sci. USA

Integrated metabolic control of food intake

Brain Res. Bull.

Fuel metabolism and appetite control

Appetite and Body Weight Regulation: Sugar, Fat, and Macronutrient Substitutes

Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus—Relationship with NPY neurones

NeuroReport

Weight-reducing effects of the plasma protein encoded by the obese gene

Science

Localization of leptin receptor mRNA splice variants in murine peripheral tissues by RT-PCR andin situ

Biochem. Biophys. Res. Commun.

Localization of leptin receptor mRNA expression in mouse brain

NeuroReport

Regular Article
Leptin Indirectly Affects Estrous Cycles by Increasing Metabolic Fuel Oxidation☆