Transient loss of satiety effects of leptin in middle-aged male mice.

Extensive research is undertaken in rodents to determine the mechanism underlying obesity-induced leptin resistance. While body weight is generally tightly controlled in these studies, the effect of age of experimental animals has received less attention. Specifically, there has been little investigation into leptin regulation of food intake in middle-aged animals, which is a period of particular relevance for weight gain in humans.

Circadian patterns of behaviour change during pregnancy in mice.

Food intake and activity adapt during pregnancy to meet the increased energy demands. In comparison to non-pregnant females, pregnant mice consume more food, eating larger meals during the light phase, and reduce physical activity. How pregnancy changes the circadian timing of behaviour was less clear.

Effect of pregnancy on the expression of nutrient-sensors and satiety hormones in mice.

Small intestinal satiation pathways involve nutrient-induced stimulation of chemoreceptors leading to release of satiety hormones from intestinal enteroendocrine cells (ECCs). Whether adaptations in these pathways contribute to increased maternal food intake during pregnancy is unknown. To determine the expression of intestinal nutrient-sensors and satiety hormone transcripts and proteins across pregnancy in mice.

High fat diet-induced maternal obesity in mice impairs peripartum maternal behaviour.

Obesity during pregnancy represents a significant health issue and can lead to increased complications during pregnancy and impairments with breastfeeding, along with long-term negative health consequences for both mother and offspring. In rodent models, diet-induced obesity (DIO) during pregnancy leads to poor outcomes for offspring. Using a DIO mouse model, consisting of feeding mice a high fat diet for 8 weeks before mating, we recapitulate the effect of high pup mortality within the first 3 days postpartum.

Sensory detection of female olfactory cues as a central regulator of energy metabolism and body weight in male mice.

Olfactory stimuli from food influence energy balance, preparing the body for digestion when food is consumed. Social chemosensory cues predict subsequent energetic changes required for social interactions and could be an additional sensory input influencing energy balance. We show that exposure to female chemostimuli increases metabolic rate in male mice and reduces body weight and adipose tissue expansion when mice are fed a high-fat diet.

Mechanisms of Lactation-induced Infertility in Female Mice.

Lactation in mammals is associated with a period of infertility, which serves to direct maternal metabolic resources toward caring for the newborn offspring rather than supporting another pregnancy. This lactational infertility is characterized by reduced pulsatile luteinizing hormone (LH) secretion and lack of ovulation. The mechanisms mediating suppression of LH secretion during lactation are unclear.

Pups and prolactin are rewarding to virgin female and pregnant mice.

Maternal interactions with offspring are highly rewarding, which reinforces expression of essential caregiving behaviours that promote offspring survival. In rats, the rewarding effect of pups depends on reproductive state, with lactating females specifically developing strong preferences for pup-associated contexts. Whether this also occurs in mice is unknown, hence we aimed to characterise pup-related preference across reproductive states in female mice.

Case-control study of prolactin and placental lactogen in SGA pregnancies.

Unlabelled: Prolactin and placental lactogens increase during pregnancy and are involved with many aspects of maternal metabolic adaptation to pregnancy, likely to impact on fetal growth. The aim of this study was to determine whether maternal plasma prolactin or placental lactogen concentrations at 20 weeks of gestation were associated with later birth of small-for-gestational-age babies (SGA). In a nested case-control study, prolactin and placental lactogen in plasma samples obtained at 20 weeks of gestation were compared between 40 women who gave birth to SGA babies and 40 women with uncomplicated pregnancies and size appropriate-for-gestation-age (AGA) babies.

Prolactin-Induced Adaptation in Glucose Homeostasis in Mouse Pregnancy Is Mediated by the Pancreas and Not in the Forebrain.

Adaptive changes in glucose homeostasis during pregnancy require proliferation of insulin-secreting beta-cells in the pancreas, together with increased sensitivity for glucose-stimulated insulin secretion. Increased concentrations of maternal prolactin/placental lactogen contribute to these changes, but the site of action remains uncertain. Use of Cre-lox technology has generated pancreas-specific prolactin receptor (Prlr) knockouts that demonstrate the development of a gestational diabetic like state.

Maternal adaptations to food intake across pregnancy: Central and peripheral mechanisms.

A sufficient and balanced maternal diet is critical to meet the nutritional demands of the developing fetus and to facilitate deposition of fat reserves for lactation. Multiple adaptations occur to meet these energy requirements, including reductions in energy expenditure and increases in maternal food intake. The central nervous system plays a vital role in the regulation of food intake and energy homeostasis and responds to multiple metabolic and nutrient cues, including those arising from the gastrointestinal tract.

Changes in maternal motivation across reproductive states in mice: A role for prolactin receptor activation on GABA neurons.

The survival of newborn offspring in mammals is dependent on sustained maternal care. Mammalian mothers are highly motivated to interact with and care for offspring, however, it is unclear how hormonal signals act on neural circuitry to promote maternal motivation during the transition to motherhood. In this study we aimed to establish methods that enable us to evaluate change in maternal motivation across the reproductive life cycle in female mice.

Central actions of insulin during pregnancy and lactation.

Pregnancy and lactation are highly metabolically demanding states. Maternal glucose is a key fuel source for the growth and development of the fetus, as well as for the production of milk during lactation. Hence, the maternal body undergoes major adaptations in the systems regulating glucose homeostasis to cope with the increased demand for glucose.

Metabolic functions of prolactin: Physiological and pathological aspects.

Prolactin is named after its vital role of promoting milk production during lactation, although it has been implicated in multiple functions within the body, including metabolism and energy homeostasis. Prolactin has been hypothesised to play a key role in driving many of the adaptations of the maternal body to allow the mother to meet the physiological demands of both pregnancy and lactation, including the high energetic demands of the growing foetus followed by milk production to support the offspring after birth. Prolactin receptors are found in many tissues involved in metabolism and food intake, such as the pancreas, liver, hypothalamus, small intestine and adipose tissue.

Pregnancy-related plasticity of gastric vagal afferent signals in mice.

Gastric vagal afferents (GVAs) sense food-related mechanical stimuli and signal to the central nervous system, to integrate control of meal termination. Pregnancy is characterized by increased maternal food intake, which is essential for normal fetal growth and to maximize progeny survival and health. However, it is unknown whether GVA function is altered during pregnancy to promote food intake.

Acute effects of prolactin on hypothalamic prolactin receptor expressing neurones in the mouse.

In addition to its critical role in lactation, the anterior pituitary hormone prolactin also influences a broad range of other physiological processes. In particular, widespread expression of prolactin receptor (Prlr) in the brain has highlighted pleiotropic roles for prolactin in regulating neuronal function, including maternal behaviour, reproduction and energy balance. Research into the central actions of prolactin has predominately focused on effects on gene transcription via the canonical JAK2/STAT5; however, it is evident that prolactin can exert rapid actions to stimulate activity in specific populations of neurones.

Neurophysiological and cognitive changes in pregnancy.

The hormonal fluctuations in pregnancy drive a wide range of adaptive changes in the maternal brain. These range from specific neurophysiological changes in the patterns of activity of individual neuronal populations, through to complete modification of circuit characteristics leading to fundamental changes in behavior. From a neurologic perspective, the key hormone changes are those of the sex steroids, estradiol and progesterone, secreted first from the ovary and then from the placenta, the adrenal glucocorticoid cortisol, as well as the anterior pituitary peptide hormone prolactin and its pregnancy-specific homolog placental lactogen.

Impaired prolactin transport into the brain and functional responses to prolactin in aged male mice.

Ageing is related to changes in a number of endocrine systems that impact on the central actions of hormones. The anterior pituitary hormone prolactin is present in the circulation in both males and females, with widespread expression of the prolactin receptor throughout the forebrain. We aimed to investigate prolactin transport into the brain, as well as circulating levels of prolactin and functional responses to prolactin, in aged male mice (23 months).

The role of prolactin in co-ordinating fertility and metabolic adaptations during reproduction.

Mammalian pregnancy and lactation is accompanied by a period of infertility that takes place in the midst of a sustained increase in food intake. Indeed, successful reproduction in females is dependent on co-ordination of the distinct systems that regulate reproduction and metabolism. Rather than arising from different mechanisms during pregnancy and lactation, we propose that elevations in lactogenic hormones (predominant among these being prolactin and the placental lactogens), are ideally placed to influence both of these systems at the appropriate time.

Chronic high prolactin levels impact on gene expression at discrete hypothalamic nuclei involved in food intake.

To study the pathological effects of continuous hyperprolactinemia on food intake mechanisms we used female mice that lack dopamine D2 receptors in lactotropes (lacDrd2KO). These mice had lifelong hyperprolactinemia, increased food intake, and gradual development of obesity from 5 to 10 months of age. Ongoing endogenous prolactin signaling in lacDrd2KO mice was evidenced by increased basal phosphorylation of STAT5b in hypothalamic areas related to food intake, such as the arcuate (ARN), dorsomedial (DMN), and ventromedial nuclei.

Neuroendocrinology and Adaptive Physiology of Maternal Care.

Parental care is critical for offspring survival in many species. In mammals, parental care is primarily provided through maternal care, due to obligate pregnancy and lactation constraints, although some species also show paternal and alloparental care. These behaviors are driven by specialized neural circuits that receive sensory, cortical, and hormonal input to generate a coordinated and timely change in behavior, and sustain that behavior through activation of reward pathways.

Suppression of Leptin Transport Into the Brain Contributes to Leptin Resistance During Pregnancy in the Mouse.

During pregnancy, when both food intake and circulating leptin concentrations increase, the brain becomes insensitive to leptin. The mechanism by which central leptin resistance during pregnancy emerges remains poorly understood. We investigated whether structural changes in the blood-brain barrier (BBB) or changes in carrier-mediated transport of leptin into the brain might contribute to pregnancy-induced leptin resistance.