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News Roundup

Discovery of glucose greed mechanism in brain: Coverage by Reuters, Fox News, The Globe and Mail, International Business Times, The Independent, Express, Times of India, The Nation,  Biosciencetechnology.com, SundayWorld.com, Free News Press, and Designntrend.com on “Glucokinase activity in the arcuate nucleus regulates glucose intake.”

Alzheimer’s breakthrough: Coverage by The Telegraph (UK), Stanford Medicine, News.Discovery.com, and Biosciencetechnology.com on “Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models.”

Exercise after weight loss reduces risk of type-2 diabetes: Coverage by News-medical.net, HCPlive.com, and Health Day on “Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity.”

Regenerative power of red blood stem cells: Coverage by MedicalXpress.com and Biosciencetechnology.com on “Protein tyrosine phosphatase–σ regulates hematopoietic stem cell–repopulating capacity.”

Published December 12, 2014, by Andy Koopmans

In the News

Related articles

Glucokinase activity in the arcuate nucleus regulates glucose intake
Syed Hussain, … , Steve Bloom, James Gardiner
Syed Hussain, … , Steve Bloom, James Gardiner
Published December 8, 2014
Citation Information: J Clin Invest. 2015;125(1):337-349. https://doi.org/10.1172/JCI77172.
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Research Article Endocrinology

Glucokinase activity in the arcuate nucleus regulates glucose intake

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Abstract

The brain relies on a constant supply of glucose, its primary fuel, for optimal function. A taste-independent mechanism within the CNS that promotes glucose delivery to the brain has been postulated to maintain glucose homeostasis; however, evidence for such a mechanism is lacking. Here, we determined that glucokinase activity within the hypothalamic arcuate nucleus is involved in regulation of dietary glucose intake. In fasted rats, glucokinase activity was specifically increased in the arcuate nucleus but not other regions of the hypothalamus. Moreover, pharmacologic and genetic activation of glucokinase in the arcuate nucleus of rodent models increased glucose ingestion, while decreased arcuate nucleus glucokinase activity reduced glucose intake. Pharmacologic targeting of potential downstream glucokinase effectors revealed that ATP-sensitive potassium channel and P/Q calcium channel activity are required for glucokinase-mediated glucose intake. Additionally, altered glucokinase activity affected release of the orexigenic neurotransmitter neuropeptide Y in response to glucose. Together, our results suggest that glucokinase activity in the arcuate nucleus specifically regulates glucose intake and that appetite for glucose is an important driver of overall food intake. Arcuate nucleus glucokinase activation may represent a CNS mechanism that underlies the oft-described phenomena of the “sweet tooth” and carbohydrate craving.

Authors

Syed Hussain, Errol Richardson, Yue Ma, Christopher Holton, Ivan De Backer, Niki Buckley, Waljit Dhillo, Gavin Bewick, Shuai Zhang, David Carling, Steve Bloom, James Gardiner

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Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Jenny U. Johansson, … , Taylor Loui, Katrin I. Andreasson
Jenny U. Johansson, … , Taylor Loui, Katrin I. Andreasson
Published December 8, 2014
Citation Information: J Clin Invest. 2015;125(1):350-364. https://doi.org/10.1172/JCI77487.
View: Text | PDF
Research Article Neuroscience

Prostaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models

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Abstract

Microglia, the innate immune cells of the CNS, perform critical inflammatory and noninflammatory functions that maintain normal neural function. For example, microglia clear misfolded proteins, elaborate trophic factors, and regulate and terminate toxic inflammation. In Alzheimer’s disease (AD), however, beneficial microglial functions become impaired, accelerating synaptic and neuronal loss. Better understanding of the molecular mechanisms that contribute to microglial dysfunction is an important objective for identifying potential strategies to delay progression to AD. The inflammatory cyclooxygenase/prostaglandin E2 (COX/PGE2) pathway has been implicated in preclinical AD development, both in human epidemiology studies and in transgenic rodent models of AD. Here, we evaluated murine models that recapitulate microglial responses to Aβ peptides and determined that microglia-specific deletion of the gene encoding the PGE2 receptor EP2 restores microglial chemotaxis and Aβ clearance, suppresses toxic inflammation, increases cytoprotective insulin-like growth factor 1 (IGF1) signaling, and prevents synaptic injury and memory deficits. Our findings indicate that EP2 signaling suppresses beneficial microglia functions that falter during AD development and suggest that inhibition of the COX/PGE2/EP2 immune pathway has potential as a strategy to restore healthy microglial function and prevent progression to AD.

Authors

Jenny U. Johansson, Nathaniel S. Woodling, Qian Wang, Maharshi Panchal, Xibin Liang, Angel Trueba-Saiz, Holden D. Brown, Siddhita D. Mhatre, Taylor Loui, Katrin I. Andreasson

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Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity
Paul M. Coen, … , Joseph A. Houmard, Bret H. Goodpaster
Paul M. Coen, … , Joseph A. Houmard, Bret H. Goodpaster
Published December 1, 2014
Citation Information: J Clin Invest. 2015;125(1):248-257. https://doi.org/10.1172/JCI78016.
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Clinical Medicine Clinical trials

Clinical trial demonstrates exercise following bariatric surgery improves insulin sensitivity

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Abstract

BACKGROUND. Roux-en-Y gastric bypass (RYGB) surgery causes profound weight loss and improves insulin sensitivity (SI) in obese patients. Regular exercise can also improve SI in obese individuals; however, it is unknown whether exercise and RYGB surgery–induced weight loss would additively improve SI and other cardiometabolic factors.

METHODS. We conducted a single-blind, prospective, randomized trial with 128 men and women who recently underwent RYGB surgery (within 1–3 months). Participants were randomized to either a 6-month semi-supervised moderate exercise protocol (EX, n = 66) or a health education control (CON; n = 62) intervention. Main outcomes measured included SI and glucose effectiveness (SG), which were determined from an intravenous glucose tolerance test and minimal modeling. Secondary outcomes measured were cardiorespiratory fitness (VO2 peak) and body composition. Data were analyzed using an intention-to-treat (ITT) and per-protocol (PP) approach to assess the efficacy of the exercise intervention (>120 min of exercise/week).

RESULTS. 119 (93%) participants completed the interventions, 95% for CON and 91% for EX. There was a significant decrease in body weight and fat mass for both groups (P < 0.001 for time effect). SI improved in both groups following the intervention (ITT: CON vs. EX; +1.64 vs. +2.24 min–1/μU/ml, P = 0.18 for Δ, P < 0.001 for time effect). A PP analysis revealed that exercise produced an additive SI improvement (PP: CON vs. EX; +1.57 vs. +2.69 min–1/μU/ml, P = 0.019) above that of surgery. Exercise also improved SG (ITT: CON vs. EX; +0.0023 vs. +0.0063 min–1, P = 0.009) compared with the CON group. Exercise improved cardiorespiratory fitness (VO2 peak) compared with the CON group.

CONCLUSION. Moderate exercise following RYGB surgery provides additional improvements in SI, SG, and cardiorespiratory fitness compared with a sedentary lifestyle during similar weight loss.

TRIAL REGISTRATION. clinicaltrials.gov identifier: NCT00692367.

FUNDING. This study was funded by the NIH/National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK078192) and an NIH/National Center for Research Resources/Clinical and Translational Science Award (UL1 RR024153).

Authors

Paul M. Coen, Charles J. Tanner, Nicole L. Helbling, Gabriel S. Dubis, Kazanna C. Hames, Hui Xie, George M. Eid, Maja Stefanovic-Racic, Frederico G.S. Toledo, John M. Jakicic, Joseph A. Houmard, Bret H. Goodpaster

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Protein tyrosine phosphatase–σ regulates hematopoietic stem cell–repopulating capacity
Mamle Quarmyne, … , Nelson J. Chao, John P. Chute
Mamle Quarmyne, … , Nelson J. Chao, John P. Chute
Published November 21, 2014
Citation Information: J Clin Invest. 2015;125(1):177-182. https://doi.org/10.1172/JCI77866.
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Brief Report Hematology

Protein tyrosine phosphatase–σ regulates hematopoietic stem cell–repopulating capacity

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Abstract

Hematopoietic stem cell (HSC) function is regulated by activation of receptor tyrosine kinases (RTKs). Receptor protein tyrosine phosphatases (PTPs) counterbalance RTK signaling; however, the functions of receptor PTPs in HSCs remain incompletely understood. We found that a receptor PTP, PTPσ, was substantially overexpressed in mouse and human HSCs compared with more mature hematopoietic cells. Competitive transplantation of bone marrow cells from PTPσ-deficient mice revealed that the loss of PTPσ substantially increased long-term HSC-repopulating capacity compared with BM cells from control mice. While HSCs from PTPσ-deficient mice had no apparent alterations in cell-cycle status, apoptosis, or homing capacity, these HSCs exhibited increased levels of activated RAC1, a RhoGTPase that regulates HSC engraftment capacity. shRNA-mediated silencing of PTPσ also increased activated RAC1 levels in wild-type HSCs. Functionally, PTPσ-deficient BM cells displayed increased cobblestone area–forming cell (CAFC) capacity and augmented transendothelial migration capacity, which was abrogated by RAC inhibition. Specific selection of human cord blood CD34+CD38–CD45RA–lin– PTPσ– cells substantially increased the repopulating capacity of human HSCs compared with CD34+CD38–CD45RA–lin– cells and CD34+CD38–CD45RA–lin–PTPσ+ cells. Our results demonstrate that PTPσ regulates HSC functional capacity via RAC1 inhibition and suggest that selecting for PTPσ-negative human HSCs may be an effective strategy for enriching human HSCs for transplantation.

Authors

Mamle Quarmyne, Phuong L. Doan, Heather A. Himburg, Xiao Yan, Mai Nakamura, Liman Zhao, Nelson J. Chao, John P. Chute

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