Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 10/2014

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

Published in: Diabetologia | Issue 10/2014

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
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
2.
American Diabetes Association (2005) Diagnosis and classification of diabetes mellitus. Diabetes Care 28(Suppl 1) :S37–S42
3.
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
4.
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
5.
Pocai A, Lam TK, Gutierrez-Juarez R et al (2005) Hypothalamic K(ATP) channels control hepatic glucose production. Nature 434:1026–1031PubMedCrossRef
6.
Marino JS, Xu Y, Hill JW (2011) Central insulin and leptin-mediated autonomic control of glucose homeostasis. Trends Endocrinol Metab 22:275–285PubMed
7.
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
8.
Goffin V, Binart N, Touraine P, Kelly PA (2002) Prolactin: the new biology of an old hormone. Annu Rev Physiol 64:47–67PubMedCrossRef
9.
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.
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.
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.
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
Metadata
Title
Central prolactin receptors (PRLRs) regulate hepatic insulin sensitivity in mice via signal transducer and activator of transcription 5 (STAT5) and the vagus nerve
Publication date
01-10-2014
Published in
Diabetologia / Issue 10/2014
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-014-3336-3

Other articles of this Issue 10/2014

Diabetologia 10/2014 Go to the issue

Erratum

Erratum to: Mig6 haploinsufficiency protects mice against streptozotocin-induced diabetes

Article

Durable change in glycaemic control following intensive management of type 2 diabetes in the ACCORD clinical trial

Commentary

Diabetes and bone fracture: risk factors for old and young

Article

Norathyriol reverses obesity- and high-fat-diet-induced insulin resistance in mice through inhibition of PTP1B

Article

Glucagon regulates orexin A secretion in humans and rodents

Letter

An explanation for recent discrepancies in levels of human circulating betatrophin

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits