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Central prolactin receptors (PRLRs) regulate hepatic insulin sensitivity in mice via signal transducer and activator of transcription 5 (STAT5) and the vagus nerve

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Abstract

Aims/hypothesis

Recent studies have revealed the crucial role of the central nervous system (CNS), especially the hypothalamus, in the regulation of insulin sensitivity in peripheral tissues. The aim of our current study was to investigate the possible involvement of hypothalamic prolactin receptors (PRLRs) in the regulation of hepatic insulin sensitivity.

Methods

We employed overexpression of PRLRs in mouse hypothalamus via intracerebroventricular injection of adenovirus expressing PRLR and inhibition of PRLRs via adenovirus expressing short-hairpin RNA (shRNA) specific for PRLRs in vivo. Selective hepatic vagotomy was employed to verify the important role of the vagus nerve in mediating signals from the brain to peripheral organs. In addition, a genetic insulin-resistant animal model, the db/db mouse, was used in our study to investigate the role of hypothalamic PRLRs in regulating whole-body insulin sensitivity.

Results

Overexpression of PRLRs in the hypothalamus improved hepatic insulin sensitivity in mice and inhibition of hypothalamic PRLRs had the opposite effect. In addition, we demonstrated that hypothalamic PRLR-improved insulin sensitivity was significantly attenuated by inhibiting the activity of signal transducer and activator of transcription 5 (STAT5) in the CNS and by selective hepatic vagotomy. Finally, overexpression of PRLRs significantly ameliorated insulin resistance in db/db mice.

Conclusions/interpretation

Our study identifies a novel central pathway involved in the regulation of hepatic insulin sensitivity, mediated by hypothalamic PRLR/STAT5 signalling and the vagus nerve, thus demonstrating an important role for hypothalamic PRLRs under conditions of insulin resistance.

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Abbreviations

CNS:

Central nervous system

ERK:

Extracellular signal-related kinase

GFP:

Green fluorescent protein

GTT:

Glucose tolerance test

icv:

Intracerebroventricular

IF:

Immunofluorescence

IR:

Insulin receptor

ITT:

Insulin tolerance test

PRLR:

Prolactin receptor

shRNA:

Short-hairpin RNA

STAT5:

Signal transducer and activator of transcription 5

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Acknowledgements

We thank W. Qiao (Institute of Neuroscience, Shanghai, China) for assistance with materials.

Funding

This work was supported by grants from the National Natural Science Foundation (81130076, 31271269, 81100615, 30890043, 81390350 and 81300659), Ministry of Science and Technology of China (973 Program 2010CB912502), International S&T Cooperation Program of China (Singapore 2014DFG32470), China National Funds for Distinguished Young Scientists (81325005), Basic Research Project of Shanghai Science and Technology Commission (13JC1409000), Key Program of Shanghai Scientific and Technological Innovation Action Plan (10JC1416900), the Knowledge Innovation Program of CAS (KSCX2-EW-R-09) and Chinese Academy of Sciences-funded project (2011KIP307). FG was also supported by the One Hundred Talents Program of the Chinese Academy of Sciences. FX was supported by the China Postdoctoral Science Foundation funded project (2012M520950 and 2013T60473) and a Chinese Academy of Sciences-funded project (2013KIP310).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

All authors contributed to the conception and design or the analysis and interpretation of data, and to drafting the article or revising it critically for intellectual content. All authors gave final approval of the version to be published. FG is responsible for the integrity of the work as a whole.

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Correspondence to Feifan Guo.

Additional information

Fei Xiao, Tingting Xia and Ziquan Lv contributed equally to this study.

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Xiao, F., Xia, T., Lv, Z. et al. Central prolactin receptors (PRLRs) regulate hepatic insulin sensitivity in mice via signal transducer and activator of transcription 5 (STAT5) and the vagus nerve. Diabetologia 57, 2136–2144 (2014). https://doi.org/10.1007/s00125-014-3336-3

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