The beneficial metabolic actions of prolactin

Abstract

The role of prolactin (PRL) favoring metabolic homeostasis is supported by multiple preclinical and clinical studies. PRL levels are key to explaining the direction of its actions. In contrast with the negative outcomes associated with very high (>100 μg/L) and very low (<7 μg/L) PRL levels, moderately high PRL levels, both within but also above the classically considered physiological range are beneficial for metabolism and have been defined as HomeoFIT-PRL. In animal models, HomeoFIT-PRL levels counteract insulin resistance, glucose intolerance, adipose tissue hypertrophy and fatty liver; and in humans associate with reduced prevalence of insulin resistance, fatty liver, glucose intolerance, metabolic syndrome, reduced adipocyte hypertrophy, and protection from type 2 diabetes development. The beneficial actions of PRL can be explained by its positive effects on main metabolic organs including the pancreas, liver, adipose tissue, and hypothalamus. Here, we briefly review work supporting PRL as a promoter of metabolic homeostasis in rodents and humans, the PRL levels associated with metabolic protection, and the proposed mechanisms involved. Finally, we discuss the possibility of using drugs elevating PRL for the treatment of metabolic diseases.

Keywords: homeoFIT-PRL; homeorhetic response; insulin resistance; metabolic homeostasis; metabolically healthy and unhealthy obesity; prolactin levels.

Figure 1

Elevated prolactin levels are part of a homeorhetic response upon metabolic challenges. A challenged metabolic state can be either physiological or pathological; in both cases a homeorhetic response includes elevated prolactin (PRL) levels, allowing a series of metabolic adaptations to deal with the physio-pathological demand. In a physiological challenge, such as pregnancy, lactation, or stress, this response leads to a new physiological set point (green arrows), whereas in a pathological challenge, such as obesity, it leads to a milder disease or protection from disease risk (yellow arrows, left side of figure). If the homeorhetic response fails, PRL levels do not rise and remain low instead, leading to altered physiological states (i.e., gestational diabetes mellitus, GDM, lactation insufficiency, LI, anxiety) (yellow arrows, right side of figure), or to aggravated disease with higher disease risk or prevalence (red arrows, right side of figure). MS, metabolic syndrome, T2D, type 2 diabetes, NAFLD, non-alcoholic fatty liver disease; MUHO, metabolically unhealthy obesity. Created in BioRender.com.

Figure 2

Mechanisms of prolactin’s beneficial metabolic actions. Prolactin (PRL) promotes metabolic homeostasis acting on the main metabolic tissues. In white adipose tissue, PRL reduces adipocyte size by stimulating lipolysis and reducing LPL activity, preventing lipid uptake. Also, it stimulates insulin sensitivity by activating PPARg and Xbp1s and promotes adipogenesis by activating CEBP/b and PPARg, favoring the healthy expansion of adipose tissue by hyperplasia vs hypertrophy in obesity conditions. In brown adipose tissue (BAT), PRL promotes adipocyte differentiation and BAT formation and activity in newborns. In liver, PRL promotes insulin sensitivity by its canonical signaling STAT5, and by activation of IRS1 and AKT. PRL also reduces liver lipid accumulation by reducing the activity of SCD1 and CD36, preventing aggravated fatty liver in NAFLD. In pancreas, PRL promotes β-cell proliferation, inhibits their apoptosis, and elicits glucose-induced insulin secretion. In hypothalamus, PRL promotes dopamine release and stimulates leptin signaling, inducing hypothalamus-mediated liver insulin sensitivity. LPL, lipoprotein lipase; PPARg; peroxisome proliferator-activated receptor-g; Xbp1s, spliced form of X-box-binding protein-1; CEBP/b, CCAAT/enhancer-binding protein beta; PRLR, prolactin receptor; IR, insulin receptor; IRS1, insulin receptor substrate 1; AKT, Protein kinase B; SCD1, stearoyl-CoA desaturase 1; CD36, fatty acid translocase; Tph1, tryptophan hydroxylase 1; 5-HT, serotonin; OPG, osteoprotegerin; RANKL, receptor activator of NF-kB ligand; Foxm1, forkhead box M1; MafB, MAF BZIP transcription factor B. Created in BioRender.com.