Calorie restriction-mediated restoration of hypothalamic signal transducer and activator of transcription 3 (STAT3) phosphorylation is not effective for lowering the body weight set point in IRS-2 knockout obese mice

Satoko Senda, Atsushi Inoue, Arshad Mahmood, Ryo Suzuki, Nozomu Kamei, Naoto Kubota, Taku Watanabe, Masashi Aoyama, Allah Nawaz, Yoshiaki Ohkuma, Koichi Tsuneyama, Yukiko Koshimizu, Isao Usui, Kumiko Saeki, Takashi Kadowaki, Kazuyuki Tobe*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Aim/hypothesis: Lowering the body weight set point is a prerequisite for the maintenance of reduced body weight. In this context, obesity is known to be strongly linked to leptin resistance, and it remains to be clarified whether recovery from leptin resistance might lower the body weight set point to allow sustained body weight loss. Methods: Obese IRS-2 knockout (IRS-2−/−) mice were subjected to calorie restriction (CR) or β3-adrenergic receptor (AR) agonist treatment. The physiological effects of leptin, hypothalamic leptin signaling, and alterations of the body weight set point were evaluated. Results: In the CR mice, recovery from acquired leptin resistance was observed, as shown by the restoration of the suppressive effects of leptin on food intake and weight gain, as well as the recovery of signal transducer and activator of transcription 3 (STAT3) phosphorylation. Nevertheless, the body weight quickly rebounded to the original body weight after cessation of the CR, suggesting that CR failed to overcome the primary defect in IRS-2/phosphatidylinositol 3-kinase (PI3K) signaling. On the other hand, after 2 weeks β3-AR agonist treatment, the mice began to lose body weight, indicating that the treatment was able to overcome the primary defect in IRS-2/PI3K signaling and lower the body weight set point. Conclusions/interpretation: Recovery of acquired leptin resistance does not lead to a resetting of the body weight set point in obese IRS-2/PI3K-defective mice. β3-AR agonist treatment may act on some pathways distal to or independent of PI3K and/or STAT3, inducing resetting of the body weight set point.

Original languageEnglish
Pages (from-to)321-335
Number of pages15
JournalDiabetology International
Volume6
Issue number4
DOIs
StatePublished - 2015/12/01

Keywords

  • Body weight set point
  • Calorie restriction
  • IRS-2 mice
  • Leptin resistance
  • Signal transducer and activator of transcription 3 (STAT3)
  • β3-adrenergic receptor agonist

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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