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01.10.2014 | Article

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

verfasst von: Fei Xiao, Tingting Xia, Ziquan Lv, Qian Zhang, Yuzhong Xiao, Junjie Yu, Hao Liu, Jiali Deng, Yajie Guo, Chunxia Wang, Kai Li, Bin Liu, Shanghai Chen, Feifan Guo

Erschienen in: Diabetologia | Ausgabe 10/2014

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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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Chen L, Magliano DJ, Zimmet PZ (2012) The worldwide epidemiology of type 2 diabetes mellitus–present and future perspectives. Nat Rev Endocrinol 8:228–236CrossRef

American Diabetes Association (2005) Diagnosis and classification of diabetes mellitus. Diabetes Care 28(Suppl 1) :S37–S42

Knight CM, Gutierrez-Juarez R, Lam TK et al (2011) Mediobasal hypothalamic SIRT1 is essential for resveratrol’s effects on insulin action in rats. Diabetes 60:2691–2700PubMedCentralPubMedCrossRef

Lam TK, Pocai A, Gutierrez-Juarez R et al (2005) Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11:320–327PubMedCrossRef

Pocai A, Lam TK, Gutierrez-Juarez R et al (2005) Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026–1031PubMedCrossRef

Marino JS, Xu Y, Hill JW (2011) Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol Metab 22:275–285PubMed

Lee JY, Muenzberg H, Gavrilova O et al (2008) Loss of cytokine-STAT5 signaling in the CNS and pituitary gland alters energy balance and leads to obesity. PLoS One 3:e1639PubMedCentralPubMedCrossRef

Goffin V, Binart N, Touraine P, Kelly PA (2002) Prolactin: the new biology of an old hormone. Annu Rev Physiol 64:47–67PubMedCrossRef

Binart N, Bachelot A, Bouilly J (2010) Impact of prolactin receptor isoforms on reproduction. Trends Endocrinol Metab 21:362–368PubMedCrossRef

10.

Freemark M, Avril I, Fleenor D et al (2002) Targeted deletion of the PRL receptor: effects on islet development, insulin production, and glucose tolerance. Endocrinology 143:1378–1385PubMedCrossRef

11.

Amaral ME, Cunha DA, Anhe GF et al (2004) Participation of prolactin receptors and phosphatidylinositol 3-kinase and MAP kinase pathways in the increase in pancreatic islet mass and sensitivity to glucose during pregnancy. J Endocrinol 183:469–476PubMedCrossRef

12.

Huang C, Snider F, Cross JC (2009) Prolactin receptor is required for normal glucose homeostasis and modulation of beta-cell mass during pregnancy. Endocrinology 150:1618–1626PubMedCrossRef

13.

Yu J, Xiao F, Zhang Q et al (2013) PRLR regulates hepatic insulin sensitivity in mice via STAT5. Diabetes 62:3103–3113PubMedCentralPubMedCrossRef

14.

Chiu S, Wise PM (1994) Prolactin receptor mRNA localization in the hypothalamus by in situ hybridization. J Neuroendocrinol 6:191–199PubMedCrossRef

15.

Pi XJ, Grattan DR (1999) Increased expression of both short and long forms of prolactin receptor mRNA in hypothalamic nuclei of lactating rats. J Mol Endocrinol 23:13–22PubMedCrossRef

16.

Augustine RA, Kokay IC, Andrews ZB, Ladyman SR, Grattan DR (2003) Quantitation of prolactin receptor mRNA in the maternal rat brain during pregnancy and lactation. J Mol Endocrinol 31:221–232PubMedCrossRef

17.

Pi XJ, Grattan DR (1998) Differential expression of the two forms of prolactin receptor mRNA within microdissected hypothalamic nuclei of the rat. Brain Res Mol Brain Res 59:1–12PubMedCrossRef

18.

Park S, Kang S, Lee HW, Ko BS (2012) Central prolactin modulates insulin sensitivity and insulin secretion in diabetic rats. Neuroendocrinology 95:332–343PubMedCrossRef

19.

Purkayastha S, Zhang H, Zhang G et al (2011) Neural dysregulation of peripheral insulin action and blood pressure by brain endoplasmic reticulum stress. Proc Natl Acad Sci U S A 108:2939–2944PubMedCentralPubMedCrossRef

20.

Ueda H, Ikegami H, Kawaguchi Y et al (2000) Age-dependent changes in phenotypes and candidate gene analysis in a polygenic animal model of Type II diabetes mellitus; NSY mouse. Diabetologia 43:932–938PubMedCrossRef

21.

Wang Q, Jiang L, Wang J et al (2009) Abrogation of hepatic ATP-citrate lyase protects against fatty liver and ameliorates hyperglycemia in leptin receptor-deficient mice. Hepatology 49:1166–1175PubMedCrossRef

22.

Xiao F, Huang Z, Li H et al (2011) Leucine deprivation increases hepatic insulin sensitivity via GCN2/mTOR/S6K1 and AMPK pathways. Diabetes 60:746–756PubMedCentralPubMedCrossRef

23.

Cheng Y, Zhang Q, Meng Q et al (2011) Leucine deprivation stimulates fat loss via increasing CRH expression in the hypothalamus and activating the sympathetic nervous system. Mol Endocrinol (Baltimore) 25:1624–1635CrossRef

24.

Guo F, Cavener DR (2007) The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. Cell Metab 5:103–114PubMedCrossRef

25.

Saltiel AR, Kahn CR (2001) Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414:799–806PubMedCrossRef

26.

Yip SH, Eguchi R, Grattan DR, Bunn SJ (2012) Prolactin signalling in the mouse hypothalamus is primarily mediated by signal transducer and activator of transcription factor 5b but not 5a. J Neuroendocrinol 24:1484–1491PubMedCrossRef

27.

Ono H, Pocai A, Wang Y et al (2008) Activation of hypothalamic S6 kinase mediates diet-induced hepatic insulin resistance in rats. J Clin Invest 118:2959–2968PubMedCentralPubMed

28.

Kodama H, Fujita M, Yamaguchi I (1994) Development of hyperglycaemia and insulin resistance in conscious genetically diabetic (C57BL/KsJ-db/db) mice. Diabetologia 37:739–744PubMedCrossRef

29.

Posner BI, Kelly PA, Friesen HG (1975) Prolactin receptors in rat liver: possible induction by prolactin. Science (New York) 188:57–59CrossRef

30.

Boutin JM, Jolicoeur C, Okamura H et al (1988) Cloning and expression of the rat prolactin receptor, a member of the growth hormone/prolactin receptor gene family. Cell 53:69–77PubMedCrossRef

31.

Bouilly J, Sonigo C, Auffret J, Gibori G, Binart N (2012) Prolactin signaling mechanisms in ovary. Mol Cell Endocrinol 356:80–87PubMedCrossRef

32.

Furth PA, Nakles RE, Millman S, Diaz-Cruz ES, Cabrera MC (2011) Signal transducer and activator of transcription 5 as a key signaling pathway in normal mammary gland developmental biology and breast cancer. Breast Cancer Res 13:220PubMedCentralPubMedCrossRef

33.

White UA, Stephens JM (2010) Transcriptional factors that promote formation of white adipose tissue. Mol Cell Endocrinol 318:10–14PubMedCentralPubMedCrossRef

34.

Cui Y, Hosui A, Sun R et al (2007) Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration. Hepatology 46:504–513PubMedCrossRef

35.

Filippi BM, Yang CS, Tang C, Lam TK (2012) Insulin activates Erk1/2 signaling in the dorsal vagal complex to inhibit glucose production. Cell Metab 16:500–510PubMedCrossRef

36.

Pocai A, Obici S, Schwartz GJ, Rossetti L (2005) A brain-liver circuit regulates glucose homeostasis. Cell Metab 1:53–61PubMedCrossRef

37.

van den Hoek AM, Voshol PJ, Karnekamp BN et al (2004) Intracerebroventricular neuropeptide Y infusion precludes inhibition of glucose and VLDL production by insulin. Diabetes 53:2529–2534PubMedCrossRef

38.

Zhang Q, Yu J, Liu B et al (2013) Central activating transcription factor 4 (ATF4) regulates hepatic insulin resistance in mice via S6K1 signaling and the vagus nerve. Diabetes 62:2230–2239PubMedCentralPubMedCrossRef

39.

Byrnes AP, Rusby JE, Wood MJA, Charlton HM (1995) Adenovirus gene-transfer causes inflammation in the brain. Neuroscience 66:1015–1024PubMedCrossRef

40.

Purkayastha S, Cai D (2013) Neuroinflammatory basis of metabolic syndrome. Mol Metab 2:356–363PubMedCentralPubMedCrossRef

41.

Moderscheim TAE, Gorba T, Pathipati P et al (2007) Prolactin is involved in glial responses following a focal injury to the juvenile rat brain. Neuroscience 145:963–973PubMedCrossRef

42.

Obici S, Zhang BB, Karkanias G, Rossetti L (2002) Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8:1376–1382PubMedCrossRef

43.

Shingo T, Gregg C, Enwere E et al (2003) Pregnancy-stimulated neurogenesis in the adult female forebrain mediated by prolactin. Science 299:117–120PubMedCrossRef

44.

Ladyman SR, Augustine RA, Grattan DR (2010) Hormone interactions regulating energy balance during pregnancy. J Neuroendocrinol 22:805–817PubMed

45.

Melo AM, Benatti RO, Ignacio-Souza LM et al (2014) Hypothalamic endoplasmic reticulum stress and insulin resistance in offspring of mice dams fed high-fat diet during pregnancy and lactation. Metab Clin Exp 63:682–692PubMedCrossRef

Titel: Central prolactin receptors (PRLRs) regulate hepatic insulin sensitivity in mice via signal transducer and activator of transcription 5 (STAT5) and the vagus nerve
verfasst von: Fei Xiao
Tingting Xia
Ziquan Lv
Qian Zhang
Yuzhong Xiao
Junjie Yu
Hao Liu
Jiali Deng
Yajie Guo
Chunxia Wang
Kai Li
Bin Liu
Shanghai Chen
Feifan Guo
Publikationsdatum: 01.10.2014
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 10/2014
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-014-3336-3

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