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Diabetes. 2018 Jul;67(7):1246-1257. doi: 10.2337/db17-1485. Epub 2018 Apr 30.

TCPTP Regulates Insulin Signaling in AgRP Neurons to Coordinate Glucose Metabolism With Feeding.

Dodd GT1,2, Lee-Young RS3,2,4, Brüning JC5,6,7,8, Tiganis T1,2,4.

Author information

1
Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Melbourne, Victoria, Australia tony.tiganis@monash.edu garron.dodd@monash.edu.
2
Department of Biochemistry and Molecular Biology, Monash University, Clayton, Melbourne, Victoria, Australia.
3
Metabolism, Diabetes and Obesity Program, Monash Biomedicine Discovery Institute, Monash University, Clayton, Melbourne, Victoria, Australia.
4
Monash Metabolic Phenotyping Facility, Monash University, Clayton, Melbourne, Victoria, Australia.
5
Department of Neuronal Control of Metabolism, Max Plank Institute for Metabolism Research, Cologne, Germany.
6
Center for Endocrinology, Diabetes, and Preventive Medicine (CEDP), University Hospital Cologne, Cologne, Germany.
7
Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases (CECAD) and Center of Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany.
8
National Center for Diabetes Research (DZD), Neuherberg, Germany.

Abstract

Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signaling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signaling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons (Agrp-Cre;Ptpn2fl/fl ) enhanced insulin sensitivity, as assessed by the increased glucose infusion rates, and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [14C]-2-deoxy-d-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice, yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp-Cre;Ptpn2fl/fl mice was corrected by IR heterozygosity (Agrp-Cre;Ptpn2fl/fl ;Insrfl/+ ), causally linking the effects on glucose metabolism with the IR signaling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signaling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting.

PMID:
29712668
DOI:
10.2337/db17-1485
[Indexed for MEDLINE]
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