Neuroendocrinology

Research Article

Persistent Leptin Signaling in the Arcuate Nucleus Impairs Hypothalamic Insulin Signaling and Glucose Homeostasis in Obese Mice

Balland E.a · Chen W.a · Tiganis T.b · Cowley M.A.a

Author affiliations

aDepartment of Physiology, Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia
bDepartment of Biochemistry and Molecular Biology , Metabolism, Diabetes and Obesity Program, Biomedicine Discovery Institute, Monash University, Clayton, VIC, Australia

Keywords: DiabetesHypothalamusInsulin resistanceLeptinObesity

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Neuroendocrinology 2019;109:374–390
https://doi.org/10.1159/000500201

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Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: February 04, 2019
Accepted: April 02, 2019
Published online: April 16, 2019
Issue release date: November 2019

Number of Print Pages: 17
Number of Figures: 6
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN

Abstract

Background: Obesity is associated with reduced physiological responses to leptin and insulin, leading to the concept of obesity-associated hormonal resistance. Objectives: Here, we demonstrate that contrary to expectations, leptin signaling not only remains functional but also is constantly activated in the arcuate nucleus of the hypothalamus (ARH) neurons of obese mice. This state of persistent response to endogenous leptin underpins the lack of response to exogenous leptin. Methods and Results: The study of combined leptin and insulin signaling demonstrates that there is a common pool of ARH neurons responding to both hormones. More importantly, we show that the constant activation of leptin receptor neurons in the ARH prevents insulin signaling in these neurons, leading to impaired glucose tolerance. Accordingly, antagonising leptin signaling in diet-induced obese (DIO) mice restores insulin signaling in the ARH and improves glucose homeostasis. Direct inhibition of PTP1B in the CNS restores arcuate insulin signaling similarly to leptin inhibition; this effect is likely to be mediated by AgRP neurons since PTP1B deletion specifically in AgRP neurons restores glucose and insulin tolerance in DIO mice. Conclusions: Finally, our results suggest that the constant activation of arcuate leptin signaling in DIO mice increases PTP1B expression, which exerts an inhibitory effect on insulin signaling leading to impaired glucose homeostasis.

© 2019 S. Karger AG, Basel



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Article / Publication Details

First-Page Preview
Abstract of Research Article

Received: February 04, 2019
Accepted: April 02, 2019
Published online: April 16, 2019
Issue release date: November 2019

Number of Print Pages: 17
Number of Figures: 6
Number of Tables: 0

ISSN: 0028-3835 (Print)
eISSN: 1423-0194 (Online)

For additional information: https://www.karger.com/NEN

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