Polycystic ovary syndrome (PCOS) is one of the most common causes of infertility in women. Approximately half of the diagnosed individuals also experience the metabolic syndrome. Central and peripheral resistance to the hormones insulin and leptin have been reported to contribute to both metabolic and reproductive dysregulation. In PCOS and preclinical PCOS animal models, circulating insulin and leptin levels are often increased in parallel with the development of hormone resistance; however, it remains uncertain whether these changes contribute to the PCOS state. In this study, we tested whether central actions of protein tyrosine phosphatase 1B (PTP1B) and suppressor of cytokine signaling 3 (SOCS3), negative regulators of insulin and leptin signaling pathways, respectively, play a role in the development of PCOS-like phenotype. A peripubertal dihydrotestosterone (DHT) excess PCOS-like mouse model was used, which exhibits both metabolic and reproductive dysfunction. Mice with knockout of the genes encoding PTP1B and SOCS3 from forebrain neurons were generated, and metabolic and reproductive functions were compared between knockout and control groups. DHT treatment induced mild insulin resistance but not leptin resistance, so the role of SOCS3 could not be tested. As expected, DHT excess abolished estrous cycles and corpora lutea presence and caused increased visceral adiposity and fasting glucose levels. Knockout mice did not show any rescue of reproductive dysfunction but did have reduced adiposity compared to the control DHT mice. These data suggest that negative regulation of central insulin signaling by PTP1B is not responsible for peripubertal DHT excess-induced reproductive impairments but may mediate its increased adiposity effects.
Journal of Endocrinology is committed to supporting researchers in demonstrating the impact of their articles published in the journal.
The two types of article metrics we measure are (i) more traditional full-text views and pdf downloads, and (ii) Altmetric data, which shows the wider impact of articles in a range of non-traditional sources, such as social media.
More information is on the Reasons to publish page.
| Sept 2018 onwards | Past Year | Past 30 Days | |
|---|---|---|---|
| Full Text Views | 183 | 178 | 17 |
| PDF Downloads | 118 | 111 | 4 |
Ancel CM, Evans MC, Kerbus RI, Wallace EG & & Anderson GM 2022 Deletion of PTP1B from brain neurons partly protects mice from diet-induced obesity and minimally improves fertility. Endocrinology 163 1–8. (https://doi.org/10.1210/endocr/bqab266)
Apridonidze T, Essah PA, Iuorno MJ & & Nestler JE 2005 Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 90 1929–1935. (https://doi.org/10.1210/jc.2004-1045)
Baker BJ, Akhtar LN & & Benveniste EN 2009 SOCS1 and SOCS3 in the control of CNS immunity. Trends in Immunology 30 392–400. (https://doi.org/10.1016/j.it.2009.07.001)
Balthasar N, Coppari R, McMinn J, Liu SM, Lee CE, Tang V, Kenny CD, McGovern RA, Chua SC, Elmquist JK, et al.2004 Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42 983–991. (https://doi.org/10.1016/j.neuron.2004.06.004)
Bence KK, Delibegovic M, Xue B, Gorgun CZ, Hotamisligil GS, Neel BG & & Kahn BB 2006 Neuronal PTP1B regulates body weight, adiposity and leptin action. Nature Medicine 12 917–924. (https://doi.org/10.1038/nm1435)
Boucsein A, Kamstra K & & Tups A 2021 Central signalling cross‐talk between insulin and leptin in glucose and energy homeostasis. Journal of Neuroendocrinology 33 e12944. (https://doi.org/10.1111/jne.12944)
Burgin KE, Waxham MN, Rickling S, Westgate SA, Mobley WC & & Kelly PT 1990 In situ hybridization histochemistry of Ca2+/calmodulin-dependent protein kinase in developing rat brain. Journal of Neuroscience 10 1788–1798. (https://doi.org/10.1523/JNEUROSCI.10-06-01788.1990)
Caldwell ASL, Middleton LJ, Jimenez M, Desai R, McMahon AC, Allan CM, Handelsman DJ & & Walters KA 2014 Characterization of reproductive, metabolic, and endocrine features of polycystic ovary syndrome in female hyperandrogenic mouse models. Endocrinology 155 3146–3159. (https://doi.org/10.1210/en.2014-1196)
Caldwell ASL, Edwards MC, Desai R, Jimenez M, Gilchrist RB, Handelsman DJ & & Walters KA 2017 Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome. PNAS 114 E3334–E3343. (https://doi.org/10.1073/pnas.1616467114)
Caligioni CS 2009 Assessing reproductive status/stages in mice. Current Protocols in Neuroscience 48 8. (https://doi.org/10.1002/0471142301.nsa04is48)
Cano G, Hernan SL & & Sved AF 2021 Centrally projecting Edinger-Westphal nucleus in the control of sympathetic outflow and energy homeostasis. Brain Sciences 11 1005. (https://doi.org/10.3390/brainsci11081005)
Casanova E, Fehsenfeld S, Mantamadiotis T, Lemberger T, Greiner E, Stewart AF & & Schütz G 2001 A CamKIIα iCre BAC allows brain-specific gene inactivation. Genesis 31 37–42. (https://doi.org/10.1002/gene.1078)
Childs GV, Odle AK, MacNicol MC & & MacNicol AM 2021 The importance of leptin to reproduction. Endocrinology 162 1–18. (https://doi.org/10.1210/endocr/bqaa204)
Croker BA, Krebs DL, Zhang JG, Wormald S, Willson TA, Stanley EG, Robb L, Greenhalgh CJ, Förster I, Clausen BE, et al.2003 SOCS3 negatively regulates IL-6 signaling in vivo. Nature Immunology 4 540–545. (https://doi.org/10.1038/ni931)
Dragatsis I & & Zeitlin S 2000 CaMKIIalpha-cre transgene expression and recombination patterns in the mouse brain. Genesis 26 133–135. (https://doi.org/10.1002/(SICI)1526-968X(200002)26:2<133::AID-GENE10>3.0.CO;2-V)
Evans MC & & Anderson GM 2017 Neuroendocrine integration of nutritional signals on reproduction. Journal of Molecular Endocrinology 58 R107–R128. (https://doi.org/10.1530/JME-16-0212)
Evans MC, Lord RA & & Anderson GM 2021 Multiple leptin signalling pathways in the control of metabolism and fertility: a means to different ends? International Journal of Molecular Sciences 22 9210. (https://doi.org/10.3390/ijms22179210)
Funkat A, Massa CM, Jovanovska V, Proietto J & & Andrikopoulos S 2004 Metabolic adaptations of three inbred strains of mice (C57BL/6, DBA/2, and 129T2) in response to a high-fat diet. Journal of Nutrition 134 3264–3269. (https://doi.org/10.1093/jn/134.12.3264)
Hill JW, Elias CF, Fukuda M, Williams KW, Berglund ED, Holland WL, Cho YR, Chuang JC, Xu Y, Choi M, et al.2010 Direct insulin and leptin action on pro-opiomelanocortin neurons Is required for normal glucose homeostasis and fertility. Cell Metabolism 11 286–297. (https://doi.org/10.1016/j.cmet.2010.03.002)
Israel D & & Chua S 2010 Leptin receptor modulation of adiposity and fertility. Trends in Endocrinology and Metabolism 21 10–16. (https://doi.org/10.1016/j.tem.2009.07.004)
Koch C, Augustine RA, Steger J, Ganjam GK, Benzler J, Pracht C, Lowe C, Schwartz MW, Shepherd PR, Anderson GM, et al.2010 Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity. Journal of Neuroscience 30 16180–16187. (https://doi.org/10.1523/JNEUROSCI.3202-10.2010)
Könner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, et al.2007 Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production. Cell Metabolism 5 438–449. (https://doi.org/10.1016/j.cmet.2007.05.004)
Li X, Zhu Q, Cao Q, Chen H & & Qian P 2014 Japanese encephalitis virus upregulates the expression of SOCS3 in mouse brain and raw264.7 cells. Viruses 6 4280–4293. (https://doi.org/10.3390/v6114280)
Lian Y, Zhao F & & Wang W 2016 Central leptin resistance and hypothalamic inflammation are involved in letrozole-induced polycystic ovary syndrome rats. Biochemical and Biophysical Research Communications 476 306–312. (https://doi.org/10.1016/j.bbrc.2016.05.117)
Manaserh IH, Chikkamenahalli L, Ravi S, Dube PR, Park JJ & & Hill JW 2019 Ablating astrocyte insulin receptors leads to delayed puberty and hypogonadism in mice. PLOS Biology 17 e3000189. (https://doi.org/10.1371/journal.pbio.3000189)
McEwen HJL, Inglis MA, Quennell JH, Grattan DR & & Anderson GM 2016 Deletion of suppressor of cytokine signaling 3 from forebrain neurons delays infertility and onset of hypothalamic leptin resistance in response to a high caloric diet. Journal of Neuroscience 36 7142–7153. (https://doi.org/10.1523/JNEUROSCI.2714-14.2016)
Moore AM, Prescott M, Marshall CJ, Yip SH & & Campbell RE 2015 Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome. PNAS 112 596–601. (https://doi.org/10.1073/pnas.1415038112)
Moore AM & & Campbell RE 2016 The neuroendocrine genesis of polycystic ovary syndrome: A role for arcuate nucleus GABA neurons. Journal of Steroid Biochemistry and Molecular Biology 160 106–117. (https://doi.org/10.1016/j.jsbmb.2015.10.002)
Moore AM & & Campbell RE 2017 Polycystic ovary syndrome: understanding the role of the brain. Frontiers in Neuroendocrinology 46 1–14. (https://doi.org/10.1016/j.yfrne.2017.05.002)
Nestler JE, Jakubowicz DJ, Falcon de Vargas AF, Brik C, Quintero N & & Medina F 1998 Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. Journal of Clinical Endocrinology and Metabolism 83 2001–2005. (https://doi.org/10.1210/jcem.83.6.4886)
Peng Y, Yang H, Song J, Feng D, Na Z, Jiang H, Meng Y, Shi B & & Li D 2022 Elevated serum leptin levels as a predictive marker for polycystic ovary syndrome. Frontiers in Endocrinology 13 845165. (https://doi.org/10.3389/fendo.2022.845165)
Rotterdam ESHRE/ASRM-Sponsored PCOS Consensus Workshop Group The Rotterdam ESHRE/ASRM‐sponsored PCOS consensus workshop group 2004 revised 2003 consensus on diagnostic criteria and long‐term health risks related to polycystic ovary syndrome (PCOS) 2004. Human Reproduction 19 41–47. (https://doi.org/10.1093/humrep/deh098)
Saavedra-Peña RDM, Taylor N & & Rodeheffer MS 2022 Insights of the role of estrogen in obesity from two models of ERα deletion. Journal of Molecular Endocrinology 68 179–194. (https://doi.org/10.1530/JME-21-0260)
Salmeen A, Andersen JN, Myers MP, Tonks NK & & Barford D 2000 Molecular basis for the dephosphorylation of the activation segment of the insulin receptor by protein tyrosine phosphatase 1B. Molecular Cell 6 1401–1412. (https://doi.org/10.1016/S1097-2765(0000137-4)
Scherer T, Sakamoto K & & Buettner C 2021 Brain insulin signalling in metabolic homeostasis and disease. Nature Reviews. Endocrinology 17 468–483. (https://doi.org/10.1038/s41574-021-00498-x)
Singh J 1995 Induction of spermatogenesis by androgens in gonadotropin-deficient (hpg) mice. Endocrinology 136 5311–5321. (https://doi.org/10.1210/en.136.12.5311)
Sullivan SD & & Moenter SM 2004 Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder. PNAS 101 7129–7134. (https://doi.org/10.1073/pnas.0308058101)
Tortoriello DV, McMinn J & & Chua SC 2004 Dietary-induced obesity and hypothalamic infertility in female DBA/2J mice. Endocrinology 145 1238–1247. (https://doi.org/10.1210/en.2003-1406)
Tosi F, Negri C, Perrone F, Dorizzi R, Castello R, Bonora E & & Moghetti P 2012 Hyperinsulinemia amplifies GnRH agonist stimulated ovarian steroid secretion in women with polycystic ovary syndrome. Journal of Clinical Endocrinology and Metabolism 97 1712–1719. (https://doi.org/10.1210/jc.2011-2939)
Tsunekawa T, Banno R, Mizoguchi A, Sugiyama M, Tominaga T, Onoue T, Hagiwara D, Ito Y, Iwama S, Goto M, et al.2017 Deficiency of PTP1B aAttenuates hypothalamic inflammation via activation of the JAK2-STAT3 pathway in microglia. EBiomedicine 16 172–183. (https://doi.org/10.1016/j.ebiom.2017.01.007)
van Vugt DA, Krzemien A, Alsaadi H, Frank TC & & Reid RL 2014 Glucose-induced inhibition of the appetitive brain response to visual food cues in polycystic ovary syndrome patients. Brain Research 1558 44–56. (https://doi.org/10.1016/j.brainres.2014.02.037)
Walters KA, Bertoldo MJ & & Handelsman DJ 2018a Evidence from animal models on the pathogenesis of PCOS. Best Practice and Research. Clinical Endocrinology and Metabolism 32 271–281. (https://doi.org/10.1016/j.beem.2018.03.008)
Walters KA, Gilchrist RB, Ledger WL, Teede HJ, Handelsman DJ & & Campbell RE 2018b New perspectives on the pathogenesis of PCOS: neuroendocrine origins. Trends in Endocrinology and Metabolism 29 841–852. (https://doi.org/10.1016/j.tem.2018.08.005)
West DB, Boozer CN, Moody DL & & Atkinson RL 1992 Dietary obesity in nine inbred mouse strains. American Journal of Physiology 262 R1025–R1032. (https://doi.org/10.1152/ajpregu.1992.262.6.R1025)
Xiong T, Rodriguez Paris V, Edwards MC, Hu Y, Cochran BJ, Rye KA, Ledger WL, Padmanabhan V, Handelsman DJ, Gilchrist RB, et al.2022 Androgen signaling in adipose tissue, but less likely skeletal muscle, mediates development of metabolic traits in a PCOS mouse model. American Journal of Physiology-Endocrinology and Metabolism 323 E145–E158. (https://doi.org/10.1152/ajpendo.00418.2021)
Zuure WA, Roberts AL, Quennell JH & & Anderson GM 2013 Leptin signaling in GABA neurons, but not glutamate neurons, is required for reproductive function. Journal of Neuroscience 33 17874–17883. (https://doi.org/10.1523/JNEUROSCI.2278-13.2013)
Online ISSN: 1479-6805
Print ISSN: 0022-0795
Strengthening biomedical communities
to advance science and health
CONTACT US
Bioscientifica Ltd | Starling House | 1600 Bristol Parkway North | Bristol BS34 8YU | UK
Bioscientifica Ltd | Registered in England no 3190519
