Prolactin-induced activation of STAT5 within the hypothalamic arcuate nucleus.

Prolactin signalling within hypothalamic areas associated with the control of fertility was examined in male and lactating female rats. Following exogenous prolactin treatment, phosphorylation of STAT5 (signal transducer and activator of transcription) within the arcuate nucleus was measured using a highly sensitive immunoblotting strategy. A significant increase in phosphorylated STAT5 was detected in the arcuate nucleus of female rats compared with same-sex controls. No such effect was apparent in the males. Phosphorylation of STAT5 was not observed in the liver of either males or females. These results show that prolactin-induced intracellular signalling within the hypothalamus involves activation of the Janus tyrosine kinase/signal transducer and activator of transcription pathway, and that this signalling mechanism can be readily triggered in lactating females where prolactin receptors are known to be upregulated and fertility impaired.

Effects of prolactin on hypothalamic supraoptic neurones: evidence for modulation of STAT5 expression and electrical activity.

OBJECTIVES: The study investigated the role of prolactin (PRL) in modulating STAT5 and electrical activity of magnocellular neurones in the supraoptic (SO) nucleus of male rats. METHODS: Evidence of expression of STAT5 in the SO nucleus was investigated by immunocytochemical methods. Effect of blocking prolactin receptors on STAT 5 expression was investigated by Western blotting following transfection of SO neurones with a dominant negative mutant form of the PRL receptor. Prolactin-induced changes in electrical activity were investigated by extracellular recording in hypothalamic slices. RESULTS: A high proportion of SO neurones in male rats expressed immunoreactive STAT5. Levels of activated STAT5 within the SO nucleus of PRL-treated rats was reduced following transfection with a dominant negative mutant form of the PRL receptor, as compared to rats transfected with wild type PRL receptor. Electrophysiological recordings from the SO nucleus in horizontal brain slices showed that approximately 25% of neurones were responsive to PRL, with both inhibitory and excitatory effects being observed. Cells displaying PRL responses included pharmacologically-identified oxytocinergic neurones. CONCLUSIONS: Collectively, the results suggest that central PRL targets neurones of the SO nucleus, influencing both activation of the JAK-STAT signalling pathway and neuronal excitability. Whilst the functional significance of this interaction remains to be established, it might be important in co-ordinating oxytocin secretion with physiological events associated with changes in plasma PRL, or in mediating a feedback loop in the oxytocinergic regulation of lactotrophs.

Enhanced leptin sensitivity and attenuation of diet-induced obesity in mice with haploinsufficiency of Socs3.

Leptin is an adipocyte-derived hormone that regulates energy balance and neuroendocrine function primarily by acting on specific hypothalamic pathways. Resistance to the weight reducing effects of leptin is a feature of most cases of human and rodent obesity, yet the molecular basis of leptin resistance is poorly understood. We have previously identified suppressor of cytokine signaling-3 (Socs3) as a leptin-induced negative regulator of leptin receptor signaling and potential mediator of leptin resistance. However, due to the non-viability of mice with targeted disruption of Socs3 (ref. 6), the importance of Socs3 in leptin action in vivo was unclear. To determine the functional significance of Socs3 in energy balance in vivo we undertook studies in mice with heterozygous Socs3 deficiency (Socs3(+/-)). We report here that Socs3(+/-) mice display greater leptin sensitivity than wild-type control mice: Socs3(+/-) mice show both enhanced weight loss and increased hypothalamic leptin receptor signaling in response to exogenous leptin administration. Furthermore, Socs3(+/-) mice are significantly protected against the development of diet-induced obesity and associated metabolic complications. The level of Socs3 expression is thus a critical determinant of leptin sensitivity and obesity susceptibility in vivo and this molecule is a potential target for therapeutic intervention.