Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis

Marianna Sadagurski, X. Dong, Martin G. Myers, Morris F. White

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Insulin receptor substrates (Irs1, 2, 3 and Irs4) mediate the actions of insulin/IGF1 signaling. They have similar structure, but distinctly regulate development, growth, and metabolic homeostasis. Irs2 contributes to central metabolic sensing, partially by acting in leptin receptor (LepRb)-expressing neurons. Although Irs4 is largely restricted to the hypothalamus, its contribution to metabolic regulation is unclear because Irs4-null mice barely distinguishable from controls. We postulated that Irs2 and Irs4 synergize and complement each other in the brain. To examine this possibility, we investigated the metabolism of whole body Irs4-/y mice that lacked Irs2 in the CNS (bIrs2-/-·Irs4-/y) or only in LepRb-neurons (Lepr{increment}Irs2·Irs4-/y). bIrs2-/-·Irs4-/y mice developed severe obesity and decreased energy expenditure, along with hyperglycemia and insulin resistance. Unexpectedly, the body weight and fed blood glucose levels of Lepr{increment}Irs2·Irs4-/y mice were not different from Lepr{increment}Irs2 mice, suggesting that the functions of Irs2 and Irs4 converge upon neurons that are distinct from those expressing LepRb.

Original languageEnglish (US)
Pages (from-to)55-63
Number of pages9
JournalMolecular Metabolism
Volume3
Issue number1
DOIs
StatePublished - Feb 2014
Externally publishedYes

Fingerprint

Homeostasis
Neurons
Glucose
Insulin Receptor Substrate Proteins
Leptin Receptors
Morbid Obesity
Growth and Development
Hyperglycemia
Energy Metabolism
Hypothalamus
Insulin Resistance
Blood Glucose
Body Weight
Insulin
Brain

Keywords

  • Energy balance
  • Insulin receptor substrate 2
  • Insulin receptor substrate 4
  • Leptin
  • Nutrient homeostasis
  • Obesity

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. / Sadagurski, Marianna; Dong, X.; Myers, Martin G.; White, Morris F.

In: Molecular Metabolism, Vol. 3, No. 1, 02.2014, p. 55-63.

Research output: Contribution to journalArticle

Sadagurski, Marianna ; Dong, X. ; Myers, Martin G. ; White, Morris F. / Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. In: Molecular Metabolism. 2014 ; Vol. 3, No. 1. pp. 55-63.
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