Universität zu Köln

Dodd, Garron T., Lee-Young, Robert S., Bruening, Jens C. and Tiganis, Tony ORCID: 0000-0002-8065-9942 (2018). TCPTP Regulates Insulin Signaling in AgRP Neurons to Coordinate Glucose Metabolism With Feeding. Diabetes, 67 (7). S. 1246 - 1258. ALEXANDRIA: AMER DIABETES ASSOC. ISSN 1939-327X

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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;Ptpn2(fl/fl)) enhanced insulin sensitivity, as assessed by the increased glucose infusion rates, and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [C-14]-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;Ptpn2(fl/fl) mice was corrected by IR heterozygosity (Agrp-Cre;Ptpn2(fl/fl);Insr(fl/+)), 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Dodd, Garron T. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lee-Young, Robert S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruening, Jens C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Tiganis, Tony UNSPECIFIED orcid.org/0000-0002-8065-9942 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-182098
DOI:	10.2337/db17-1485
Journal or Publication Title:	Diabetes
Volume:	67
Number:	7
Page Range:	S. 1246 - 1258
Date:	2018
Publisher:	AMER DIABETES ASSOC
Place of Publication:	ALEXANDRIA
ISSN:	1939-327X
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language BROWN ADIPOSE-TISSUE; FATTY-ACID OXIDATION; HYPOTHALAMIC INSULIN; ADULT HUMANS; FUNCTIONAL-CHARACTERIZATION; POMC NEURONS; RECEPTOR; LEPTIN; MICE; SENSITIVITY Multiple languages Endocrinology & Metabolism Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18209