Dopamine D2 receptor antagonist counteracts hyperglycemia and insulin resistance in diet-induced obese male mice.

Obesity leads to insulin resistance (IR) and type 2 diabetes. In humans, low levels of the hormone prolactin (PRL) correlate with IR, adipose tissue (AT) dysfunction, and increased prevalence of T2D. In obese rats, PRL treatment promotes insulin sensitivity and reduces visceral AT adipocyte hypertrophy. Here, we tested whether elevating PRL levels with the prokinetic and antipsychotic drug sulpiride, an antagonist of dopamine D2 receptors, improves metabolism in high fat diet (HFD)-induced obese male mice. Sulpiride treatment (30 days) reduced hyperglycemia, IR, and the serum and pancreatic levels of triglycerides in obese mice, reduced visceral and subcutaneous AT adipocyte hypertrophy, normalized markers of visceral AT function (PRL receptor, Glut4, insulin receptor and Hif-1α), and increased glycogen stores in skeletal muscle. However, the effects of sulpiride reducing hyperglycemia were also observed in obese prolactin receptor null mice. We conclude that sulpiride reduces obesity-induced hyperglycemia by mechanisms that are independent of prolactin/prolactin receptor activity. These findings support the therapeutic potential of sulpiride against metabolic dysfunction in obesity.

Prolactin Inhibits or Stimulates the Inflammatory Response of Joint Tissues in a Cytokine-dependent Manner.

The close association between rheumatoid arthritis (RA), sex, reproductive state, and stress has long linked prolactin (PRL) to disease progression. PRL has both proinflammatory and anti-inflammatory outcomes in RA, but responsible mechanisms are not understood. Here, we show that PRL modifies in an opposite manner the proinflammatory actions of IL-1ß and TNF-α in mouse synovial fibroblasts in culture. Both IL-1ß and TNF-α upregulated the metabolic activity and the expression of proinflammatory factors (Il1b, Inos, and Il6) via the activation of the nuclear factor-κB (NF-κB) signaling pathway. However, IL-1ß increased and TNF-α decreased the levels of the long PRL receptor isoform in association with dual actions of PRL on synovial fibroblast inflammatory response. PRL reduced the proinflammatory effect and activation of NF-κB by IL-1ß but increased TNF-α-induced inflammation and NF-κB signaling. The double-faceted role of PRL against the 2 cytokines manifested also in vivo. IL-1ß or TNF-α with or without PRL were injected into the knee joints of healthy mice, and joint inflammation was monitored after 24 hours. IL-1ß and TNF-α increased the joint expression of proinflammatory factors and the infiltration of immune cells. PRL prevented the actions of IL-1ß but was either inactive or further increased the proinflammatory effect of TNF-α. We conclude that PRL exerts opposite actions on joint inflammation in males and females that depend on specific proinflammatory cytokines, the level of the PRL receptor, and the activation of NF-κB signaling. Dual actions of PRL may help balance joint inflammation in RA and provide insights for development of new treatments.