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. We review the literature examining the effects of prolactin in these various tissues and how they relate to changes in function in physiological states of high prolactin, such as pregnancy and lactation, and in pathological states of hyperprolactinaemia in the adult. In many cases, whether prolactin promotes healthy metabolism or leads to dysregulation of metabolic functions is highly dependent on the situation. Overall, although prolactin may not play a major role in regulating metabolism and body weight outside of pregnancy and lactation, it definitely has the ability to contribute to metabolic function.Fil: López Vicchi, María Felicitas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: de Winne, Catalina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Brie, Belen. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sorianello, Eleonora Mariana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ladyman, Sharon R.. University of Otago; Nueva ZelandaFil: Becu, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

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. In the ARN of young lacDrd2KO mice there were higher Prlr mRNA levels and in obese 10‐month‐old lacDrd2KO mice increased expression of the orexigenic genes Neuropeptide Y (Npy ) and Agouti‐related peptide, compared to controls. Furthermore, Npy expression was increased in the DMN, probably contributing to increased food intake and decreased expression of Uncoupling protein‐1 in brown adipose tissue, both events favoring weight gain. Leptin resistance in obese lacD2RKO mice was evidenced by its failure to lower food intake and a dampened response of STAT3 phosphorylation, specifically in the mediobasal hypothalamus. Our results suggest that pathological chronically high prolactin levels, as found in psychiatric treatments or patients with prolactinomas, may impact on specific hypothalamic nuclei altering gene expression, leptin response, and food intake.Fil: López Vicchi, María Felicitas. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Ladyman, Sharon R.. Maurice Wilkins Centre; Nueva Zelanda. University of Otago; Nueva ZelandaFil: Ornstein, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Gustafson, Papillon. University of Otago; Nueva ZelandaFil: Knowles, Penelope. University of Otago; Nueva ZelandaFil: Luque, Guillermina Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Grattan, David R.. Maurice Wilkins Centre; Nueva Zelanda. University of Otago; Nueva ZelandaFil: Becu Villalobos, Damasia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentin

From feeding one to feeding many: hormone-induced changes in bodyweight homeostasis during pregnancy

Pregnancy is associated with hyperphagia, increased fat mass, hyperleptinaemia and hyperprolactinaemia. The neuroendocrine control of bodyweight involves appetite-regulating centres in the hypothalamus, containing both orexigenic and anorexigenic neurons that express leptin receptors (LepR). In the rat, central leptin resistance develops during mid pregnancy, well after hyperphagia becomes apparent, to negate the appetite suppressing effects of leptin. We have investigated the hypothalamic response to leptin during pregnancy and examined the role of pregnancy hormones in inducing these changes. We have shown that there are multiple levels of leptin resistance during pregnancy. Despite elevated serum leptin, neuropeptide Y and agouti related peptide mRNA in the arcuate nucleus are not suppressed and may even be increased during pregnancy. LepR mRNA and leptin-induced pSTAT3 expression, however, are relatively normal in the arcuate nucleus. In contrast, both LepR and leptin-induced pSTAT3 are reduced in the ventromedial hypothalamic nucleus. Injecting α-melanocyte-stimulating hormone (α-MSH) into the brain, to bypass the first-order leptin-responsive neurons in the arcuate nucleus, also fails to suppress food intake during pregnancy, suggesting that pregnancy is also a melanocortin-resistant state. Using a pseudopregnant rat model, we have demonstrated that in addition to the changes in maternal ovarian steroid secretion, placental lactogen production is essential for the induction of leptin resistance in pregnancy. Thus, hormonal changes associated with pregnancy induce adaptive changes in the maternal hypothalamus, stimulating food intake and then allowing elevated food intake to be maintained in the face of elevated leptin levels, resulting in fat deposition to provide energy stores in preparation for the high metabolic demands of late pregnancy and lactation