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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Agouti-Related Protein / metabolism*
  • Animals
  • Carbohydrate Metabolism / physiology
  • Eating / physiology*
  • Energy Metabolism / genetics
  • Fasting
  • Gluconeogenesis / genetics*
  • Glucose / metabolism*
  • Glucose Clamp Technique
  • Insulin / metabolism*
  • Liver / metabolism
  • Mice
  • Mice, Transgenic
  • Neurons / metabolism*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / genetics
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2 / physiology*
  • Receptor, Insulin / metabolism
  • Signal Transduction / genetics


  • Agouti-Related Protein
  • Insulin
  • Receptor, Insulin
  • Protein Tyrosine Phosphatase, Non-Receptor Type 2
  • Glucose