Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact

Endocrinology

  • 207 Articles
  • 5 Posts
  • ← Previous
  • 1
  • 2
  • …
  • 17
  • 18
  • 19
  • 20
  • 21
  • Next →
The calcium-sensing receptor regulates mammary gland parathyroid hormone–related protein production and calcium transport
Joshua VanHouten, … , Margaret Neville, John J. Wysolmerski
Joshua VanHouten, … , Margaret Neville, John J. Wysolmerski
Published February 15, 2004
Citation Information: J Clin Invest. 2004;113(4):598-608. https://doi.org/10.1172/JCI18776.
View: Text | PDF

The calcium-sensing receptor regulates mammary gland parathyroid hormone–related protein production and calcium transport

  • Text
  • PDF
Abstract

The transfer of calcium from mother to milk during lactation is poorly understood. In this report, we demonstrate that parathyroid hormone–related protein (PTHrP) production and calcium transport in mammary epithelial cells are regulated by extracellular calcium acting through the calcium-sensing receptor (CaR). The CaR becomes expressed on mammary epithelial cells at the transition from pregnancy to lactation. Increasing concentrations of calcium, neomycin, and a calcimimetic compound suppress PTHrP secretion by mammary epithelial cells in vitro, whereas in vivo, systemic hypocalcemia increases PTHrP production, an effect that can be prevented by treatment with a calcimimetic. Hypocalcemia also reduces overall milk production and calcium content, while increasing milk osmolality and protein concentrations. The changes in milk calcium content, milk osmolality, and milk protein concentration were mitigated by calcimimetic infusions. Finally, in a three-dimensional culture system that recapitulates the lactating alveolus, activation of the basolateral CaR increases transcellular calcium transport independent of its effect on PTHrP. We conclude that the lactating mammary gland can sense calcium and adjusts its secretion of calcium, PTHrP, and perhaps water in response to changes in extracellular calcium concentration. We believe this defines a homeostatic system that helps to match milk production to the availability of calcium.

Authors

Joshua VanHouten, Pamela Dann, Grace McGeoch, Edward M. Brown, Karen Krapcho, Margaret Neville, John J. Wysolmerski

×

Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation
Joshua N. VanHouten, … , Andrew C. Karaplis, John J. Wysolmerski
Joshua N. VanHouten, … , Andrew C. Karaplis, John J. Wysolmerski
Published February 1, 2004
Citation Information: J Clin Invest. 2004;113(3):492-492. https://doi.org/10.1172/JCI19504C1.
View: Text | PDF | Amended Article

Mammary-specific deletion of parathyroid hormone-related protein preserves bone mass during lactation

  • Text
  • PDF
Abstract

Authors

Joshua N. VanHouten, Pamela Dann, Andrew F. Stewart, Christine J. Watson, Michael Pollak, Andrew C. Karaplis, John J. Wysolmerski

×

Mosaic analysis of insulin receptor function
Tadahiro Kitamura, … , Argiris Efstratiadis, Domenico Accili
Tadahiro Kitamura, … , Argiris Efstratiadis, Domenico Accili
Published January 15, 2004
Citation Information: J Clin Invest. 2004;113(2):209-219. https://doi.org/10.1172/JCI17810.
View: Text | PDF

Mosaic analysis of insulin receptor function

  • Text
  • PDF
Abstract

Insulin promotes both metabolism and growth. However, it is unclear whether insulin-dependent growth is merely a result of its metabolic actions. Targeted ablation of insulin receptor (Insr) has not clarified this issue, because of early postnatal lethality. To examine this question, we generated mice with variable cellular mosaicism for null Insr alleles. Insr ablation in approximately 80% of cells caused extreme growth retardation, lipoatrophy, and hypoglycemia, a clinical constellation that resembles the human syndrome of leprechaunism. Insr ablation in 98% of cells, while resulting in similar growth retardation and lipoatrophy, caused diabetes without β-cell hyperplasia. The growth retardation was associated with a greater than 60-fold increase in the expression of hepatic insulin-like growth factor binding protein-1. These findings indicate that insulin regulates growth independently of metabolism and that the number of insulin receptors is an important determinant of the specificity of insulin action.

Authors

Tadahiro Kitamura, Yukari Kitamura, Jun Nakae, Antonio Giordano, Saverio Cinti, C. Ronald Kahn, Argiris Efstratiadis, Domenico Accili

×

The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions
Akito Tanoue, … , Toyoki Mori, Gozoh Tsujimoto
Akito Tanoue, … , Toyoki Mori, Gozoh Tsujimoto
Published January 15, 2004
Citation Information: J Clin Invest. 2004;113(2):302-309. https://doi.org/10.1172/JCI19656.
View: Text | PDF

The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions

  • Text
  • PDF
Abstract

The neurohypophyseal peptide [Arg8]-vasopressin (AVP) exerts major physiological actions through three distinct receptor isoforms designated V1a, V1b, and V2. Among these three subtypes, the vasopressin V1b receptor is specifically expressed in pituitary corticotrophs and mediates the stimulatory effect of vasopressin on ACTH release. To investigate the functional roles of V1b receptor subtypes in vivo, gene targeting was used to create a mouse model lacking the V1b receptor gene (V1bR–/–). Under resting conditions, circulating concentrations of ACTH and corticosterone were lower in V1bR–/– mice compared with WT mice (V1bR+/+). The normal increase in circulating ACTH levels in response to exogenous administration of AVP was impaired in V1bR–/– mice, while corticotropin-releasing hormone–stimulated ACTH release in the V1bR–/– mice was not significantly different from that in the V1bR+/+ mice. AVP-induced ACTH release from primary cultured pituitary cells in V1bR–/– mice was also blunted. Furthermore, the increase in ACTH after a forced swim stress was significantly suppressed in V1bR–/– mice. Our results clearly demonstrate that the V1b receptor plays a crucial role in regulating hypothalamic-pituitary-adrenal axis activity. It does this by maintaining ACTH and corticosterone levels, not only under stress but also under basal conditions.

Authors

Akito Tanoue, Shuji Ito, Kenji Honda, Sayuri Oshikawa, Yoko Kitagawa, Taka-aki Koshimizu, Toyoki Mori, Gozoh Tsujimoto

×

A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons
Theron A. Russell, … , Jeffrey Weiss, J. Larry Jameson
Theron A. Russell, … , Jeffrey Weiss, J. Larry Jameson
Published December 1, 2003
Citation Information: J Clin Invest. 2003;112(11):1697-1706. https://doi.org/10.1172/JCI18616.
View: Text | PDF

A murine model of autosomal dominant neurohypophyseal diabetes insipidus reveals progressive loss of vasopressin-producing neurons

  • Text
  • PDF
Abstract

Familial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant disorder caused by mutations in the arginine vasopressin (AVP) precursor. The pathogenesis of FNDI is proposed to involve mutant protein–induced loss of AVP-producing neurons. We established murine knock-in models of two different naturally occurring human mutations that cause FNDI. A mutation in the AVP signal sequence [A(–1)T] is associated with a relatively mild phenotype or delayed presentation in humans. This mutation caused no apparent phenotype in mice. In contrast, heterozygous mice expressing a mutation that truncates the AVP precursor (C67X) exhibited polyuria and polydipsia by 2 months of age and these features of DI progressively worsened with age. Studies of the paraventricular and supraoptic nuclei revealed induction of the chaperone protein BiP and progressive loss of AVP-producing neurons relative to oxytocin-producing neurons. In addition, Avp gene products were not detected in the neuronal projections, suggesting retention of WT and mutant AVP precursors within the cell bodies. In summary, this murine model of FNDI recapitulates many features of the human disorder and demonstrates that expression of the mutant AVP precursor leads to progressive neuronal cell loss.

Authors

Theron A. Russell, Masafumi Ito, Mika Ito, Richard N. Yu, Fred A. Martinson, Jeffrey Weiss, J. Larry Jameson

×

Mammary-specific deletion of parathyroid hormone–related protein preserves bone mass during lactation
Joshua N. VanHouten, … , Andrew C. Karaplis, John J. Wysolmerski
Joshua N. VanHouten, … , Andrew C. Karaplis, John J. Wysolmerski
Published November 1, 2003
Citation Information: J Clin Invest. 2003;112(9):1429-1436. https://doi.org/10.1172/JCI19504.
View: Text | PDF | Corrigendum

Mammary-specific deletion of parathyroid hormone–related protein preserves bone mass during lactation

  • Text
  • PDF
Abstract

Large amounts of calcium are transferred to offspring by milk. This demand results in negative calcium balance in lactating mothers and is associated with rapid bone loss. The mechanisms of bone loss during lactation are only partly understood. Several studies have suggested that parathyroid hormone–related protein (PTHrP) might be secreted into the circulation by the lactating mammary gland and regulate bone turnover during lactation. Because mammary development fails in the absence of PTHrP, conventional PTHrP knockout mice cannot be used to address this possibility. To examine this hypothesis, we therefore used mice carrying a β-lactoglobulin promoter-driven Cre transgene, one null PTHrP allele, and one floxed PTHrP allele. Expression of Cre specifically in mammary epithelial cells during late pregnancy and lactation resulted in efficient deletion of the PTHrP gene; mammary gland PTHrP mRNA and milk PTHrP protein were almost completely absent. Removal of PTHrP from the lactating mammary glands resulted in reductions in levels of circulating PTHrP and 1,25-dihydroxy vitamin D and urinary cAMP. In addition, bone turnover was reduced and bone loss during lactation was attenuated. We conclude that during lactation mammary epithelial cells are a source of circulating PTHrP that promotes bone loss by increasing rates of bone resorption.

Authors

Joshua N. VanHouten, Pamela Dann, Andrew F. Stewart, Christine J. Watson, Michael Pollak, Andrew C. Karaplis, John J. Wysolmerski

×

Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load
John N. Lorenz, … , Lane L. Clarke, Mitchell B. Cohen
John N. Lorenz, … , Lane L. Clarke, Mitchell B. Cohen
Published October 15, 2003
Citation Information: J Clin Invest. 2003;112(8):1244-1254. https://doi.org/10.1172/JCI18743.
View: Text | PDF

Uroguanylin knockout mice have increased blood pressure and impaired natriuretic response to enteral NaCl load

  • Text
  • PDF
Abstract

Guanylin and uroguanylin, peptides synthesized in the intestine and kidney, have been postulated to have both paracrine and endocrine functions, forming a potential enteric-renal link to coordinate salt ingestion with natriuresis. To explore the in vivo role of uroguanylin in the regulation of sodium excretion, we created gene-targeted mice in which uroguanylin gene expression had been ablated. Northern and Western analysis confirmed the absence of uroguanylin message and protein in knockout mice, and cGMP levels were decreased in the mucosa of the small intestine. Ussing chamber analysis of jejunum revealed that Na+/H+ exchanger–mediated Na+ absorption and tissue conductance was not altered in the knockout animals, but short-circuit current, an index of electrogenic anion secretion, was reduced. Renal clearance measurements showed that uroguanylin deficiency results in impaired ability to excrete an enteral load of NaCl, primarily due to an inappropriate increase in renal Na+ reabsorption. Finally, telemetric recordings of blood pressure demonstrated increased mean arterial pressure in uroguanylin knockout animals that was independent of the level of dietary salt intake. Together, these findings establish a role for uroguanylin in an enteric-renal communication axis as well as a fundamental principle of this axis in the maintenance of salt homeostasis in vivo.

Authors

John N. Lorenz, Michelle Nieman, Jenine Sabo, L. Philip Sanford, Jennifer A. Hawkins, Noeet Elitsur, Lara R. Gawenis, Lane L. Clarke, Mitchell B. Cohen

×

PKCλ in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity
Michihiro Matsumoto, … , Masato Kasuga, Tetsuo Noda
Michihiro Matsumoto, … , Masato Kasuga, Tetsuo Noda
Published September 15, 2003
Citation Information: J Clin Invest. 2003;112(6):935-944. https://doi.org/10.1172/JCI18816.
View: Text | PDF

PKCλ in liver mediates insulin-induced SREBP-1c expression and determines both hepatic lipid content and overall insulin sensitivity

  • Text
  • PDF
Abstract

PKCλ is implicated as a downstream effector of PI3K in insulin action. We show here that mice that lack PKCλ specifically in the liver (L-λKO mice), produced with the use of the Cre-loxP system, exhibit increased insulin sensitivity as well as a decreased triglyceride content and reduced expression of the sterol regulatory element–binding protein-1c (SREBP-1c) gene in the liver. Induction of the hepatic expression of Srebp1c and of its target genes involved in fatty acid/triglyceride synthesis by fasting and refeeding or by hepatic expression of an active form of PI3K was inhibited in L-λKO mice compared with that in control animals. Expression of Srebp1c induced by insulin or by active PI3K in primary cultured rat hepatocytes was inhibited by a dominant-negative form of PKCλ and was mimicked by overexpression of WT PKCλ. Restoration of PKCλ expression in the liver of L-λKO mice with the use of adenovirus-mediated gene transfer corrected the metabolic abnormalities of these animals. Hepatic PKCλ is thus a determinant of hepatic lipid content and whole-body insulin sensitivity.

Authors

Michihiro Matsumoto, Wataru Ogawa, Kazunori Akimoto, Hiroshi Inoue, Kazuaki Miyake, Kensuke Furukawa, Yoshitake Hayashi, Haruhisa Iguchi, Yasushi Matsuki, Ryuji Hiramatsu, Hitoshi Shimano, Nobuhiro Yamada, Shigeo Ohno, Masato Kasuga, Tetsuo Noda

×

Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo
Nobuyuki Shibusawa, … , Ronald N. Cohen, Fredric E. Wondisford
Nobuyuki Shibusawa, … , Ronald N. Cohen, Fredric E. Wondisford
Published August 15, 2003
Citation Information: J Clin Invest. 2003;112(4):588-597. https://doi.org/10.1172/JCI18377.
View: Text | PDF

Thyroid hormone action in the absence of thyroid hormone receptor DNA-binding in vivo

  • Text
  • PDF
Abstract

Thyroid hormone action is mediated by thyroid hormone receptors (TRs), which are members of the nuclear hormone receptor superfamily. DNA-binding is presumed to be essential for all nuclear actions of thyroid hormone. To test this hypothesis in vivo, the DNA-binding domain of TR-β was mutated within its P-box (GS mutant) using gene targeting techniques. This mutation in vitro completely abolishes TR-β DNA-binding, while preserving ligand (T3) and cofactor interactions with the receptor. Homozygous mutant (TR-βGS/GS) mice displayed abnormal T3 regulation of the hypothalamic-pituitary-thyroid axis and retina identical to abnormalities previously observed in TR-β KO (TR-β–/–) mice. However, TR-βGS/GS mutant mice maintained normal hearing at certain frequencies and did not display significant outer hair cell loss, in contrast to TR-β–/– mice. DNA-binding, therefore, is essential for many functions of the TR, including retinal development and negative feedback regulation by thyroid hormone of the hypothalamic-pituitary-thyroid axis. Inner ear development, although not completely normal, can occur in the absence of TR DNA-binding, suggesting that an alternative and perhaps novel thyroid hormone-signaling pathway may mediate these effects.

Authors

Nobuyuki Shibusawa, Koshi Hashimoto, Amisra A. Nikrodhanond, M. Charles Liberman, Meredithe L. Applebury, Xiao Hui Liao, Janet T. Robbins, Samuel Refetoff, Ronald N. Cohen, Fredric E. Wondisford

×

Deubiquitination of type 2 iodothyronine deiodinase by von Hippel–Lindau protein–interacting deubiquitinating enzymes regulates thyroid hormone activation
Cyntia Curcio-Morelli, … , Guan Wu, Antonio C. Bianco
Cyntia Curcio-Morelli, … , Guan Wu, Antonio C. Bianco
Published July 15, 2003
Citation Information: J Clin Invest. 2003;112(2):189-196. https://doi.org/10.1172/JCI18348.
View: Text | PDF

Deubiquitination of type 2 iodothyronine deiodinase by von Hippel–Lindau protein–interacting deubiquitinating enzymes regulates thyroid hormone activation

  • Text
  • PDF
Abstract

The type 2 iodothyronine deiodinase (D2) is an integral membrane ER-resident selenoenzyme that activates the pro-hormone thyroxine (T4) and supplies most of the 3,5,3′-triiodothyronine (T3) that is essential for brain development. D2 is inactivated by selective conjugation to ubiquitin, a process accelerated by T4 catalysis and essential for the maintenance of T3 homeostasis. A yeast two-hybrid screen of a human-brain library with D2 as bait identified von Hippel–Lindau protein–interacting deubiquitinating enzyme-1 (VDU1). D2 interaction with VDU1 and VDU2, a closely related deubiquitinase, was confirmed in mammalian cells. Both VDU proteins colocalize with D2 in the ER, and their coexpression prolongs D2 half-life and activity by D2 deubiquitination. VDU1, but not VDU2, is markedly increased in brown adipocytes by norepinephrine or cold exposure, further amplifying the increase in D2 activity that results from catecholamine-stimulated de novo synthesis. Thus, deubiquitination regulates the supply of active thyroid hormone to brown adipocytes and other D2-expressing cells.

Authors

Cyntia Curcio-Morelli, Ann Marie Zavacki, Marcelo Christofollete, Balazs Gereben, Beatriz C.G. de Freitas, John W. Harney, Zaibo Li, Guan Wu, Antonio C. Bianco

×
  • ← Previous
  • 1
  • 2
  • …
  • 17
  • 18
  • 19
  • 20
  • 21
  • Next →
Dynamin 2 prevents insulin granule traffic jams
Fan Fan and colleagues demonstrate that dynamin 2 is important for maintaining insulin secretion dynamics in β cells…
Published September 28, 2015
Scientific Show StopperEndocrinology

UPR stress gets β cells going
Rohit Sharma and colleagues reveal that insulin demand-induced β cell proliferation is regulated by the unfolded protein response…
Published September 21, 2015
Scientific Show StopperEndocrinology

Restricting β cell growth
Sung Hee Um and colleagues reveal that S6K1-dependent alterations of β cell size and function are independent of intrauterine growth restriction…
Published June 15, 2015
Scientific Show StopperEndocrinology

Insight into Kallmann syndrome
Anna Cariboni and colleagues demonstrate that dysfunctional SEMA3E results in gonadotropin-releasing hormone neuron deficiency…
Published May 18, 2015
Scientific Show StopperEndocrinology

L cells to the rescue
Natalia Peterson and colleagues demonstrate that increasing L cell populations in the gut improves insulin responses and glucose tolerance in a murine type 2 diabetes model…
Published December 15, 2014
Scientific Show StopperEndocrinology
Advertisement
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts