Focus on prolactin as a metabolic hormone

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New information about the effects of prolactin (PRL) on metabolic processes warrants re-evaluation of the overall metabolic actions of PRL. PRL affects metabolic homeostasis by regulating key enzymes and transporters that are associated with glucose and lipid metabolism in several target organs. In the lactating mammary gland, PRL increases the production of milk proteins, lactose and lipids. In adipose tissue, PRL generally suppresses lipid storage and adipokine release. PRL supports the growth of pancreatic islets, stimulates insulin secretion and increases citrate production in the prostate. A specific case is made for PRL in the human breast and adipose tissue, where it acts as a circulating hormone and an autocrine or paracrine factor. Although the overall effects of PRL on body composition are modest and species specific, PRL might be involved in the manifestation of insulin resistance.

Introduction

The metabolic status of an organism is finely regulated by nutritional status, energy expenditure and hormonal signals. Organs such as the pancreas, liver and adipose tissue respond to these cues and regulate metabolic homeostasis. Prolactin (PRL) is a multifunctional pituitary hormone, and PRL receptors (PRLRs) are expressed in nearly all organs. In humans, PRL is also produced at extrapituitary sites, so it is classified as a circulating hormone and an autocrine or paracrine factor. PRL has more functions than all other pituitary hormones combined. These actions can be categorized broadly as reproductive, metabolic, osmoregulatory and immunoregulatory. Since the publication of several comprehensive reviews on PRL 1, 2, 3, new information has emerged that warrants an update on its metabolic functions. In this review, we first describe the global effects of PRL on body composition, followed by its metabolic actions in four target tissues: breast, adipose, pancreas and prostate (Figure 1).

Section snippets

Global actions of PRL on body weight and adiposity

Studies on rats provide the most consistent data on the effects of PRL on body composition. Chronic elevation of PRL, induced by dopamine antagonists, daily injections of PRL and ectopic pituitaries, are associated with increased food intake and body weight, but gain in adipose-tissue mass is not well documented 4, 5, 6, 7. Suppression of PRL release by bromocriptine results in the opposite outcome, and is most effective in lactating rats and least effective in males 5, 8. Injections of PRL

Regulation of mammary-gland metabolism by PRL

PRL has a commanding role in cellular growth, differentiation, secretion and involution of the mammary gland. However, assessment of the direct metabolic actions of PRL is hampered by several limitations. First, initiation (lactogenesis) and maintenance (galactopoiesis) of lactation are complex processes that require the sequential, orchestrated actions of many hormones. PRL has a more dominant role during lactation in rabbits, rodents and humans, and a lesser role in ruminants. Second,

Metabolic and endocrine actions of PRL on adipose tissue

Adipose tissue is an active organ that plays a pivotal role in metabolic, physiological and endocrine homeostasis. Based on the notion that PRLRs are not present in adipose tissue, PRL was considered previously to be an indirect regulator of adipose tissue [23]. However, with new evidence to the contrary, this concept should be revisited. Indeed, PRLRs are present in brown and white adipose tissue from several species 11, 32, 33, 34, 35. At the protein level, the long-PRLR isoform and several

PRL as an autocrine or paracrine factor in human adipose tissue

PRL production in human adipose tissue was discovered serendipitously during studies of PRL release by human breast explants. Intended as a negative control, breast adipose tissue was found to release 10–15-times more PRL than glandular tissue [29]. PRL release from glandular tissue is inhibited by progesterone, but neither estrogen nor progesterone alters the release of PRL from adipose tissue, which indicates that regulation of PRL release is different in the two adjacent compartments. These

Effects of PRL on growth of pancreatic islets and insulin secretion

Lactogenic hormones are important regulators of the growth of pancreatic islets and their function during the perinatal period. Because a unique receptor for placental lactogens has not been identified, the general consensus is that the PRLR serves both PRL and placental lactogens. In early fetal life, the PRLR is expressed primarily in islet acinar cells and ducts, and becomes more prominent in insulin-producing and glucagon-producing cells during the perinatal and postnatal periods [53].

PRL stimulates citrate production in prostatic cells

Increased biosynthesis of citrate in the prostate gland in response to PRL is a fine example of its coordinated effects on key metabolic enzymes. As reviewed by Costello and Franklin [64], the prostate secretes unusually high levels of citrate, which has important functions in the normal gland, whereas its production is decreased markedly in prostate cancer. Unlike other cells, in which citrate is an intermediate metabolite, it is the end-product in prostate cells. As depicted in Figure 3, two

Conclusions and future directions

The metabolic actions of PRL are not confined to the lactating mammary gland. Globally, excess PRL correlates with changes in food intake and body weight in some species, although it has marginal effects on fat deposition. Emerging data indicate that PRL has a role in whole-body insulin sensitivity by stimulating insulin release and regulating adipokine release. The recent finding of lower release of PRL from human subcutaneous adipose tissue from obese compared with lean individuals indicates

Acknowledgements

This work was supported by the National Institutes of Health grants ES012212 and CA096613 (N.B.-J.), and training grant DK59803 (E.R.H. and T.D.B.).

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