Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes

Molecular Metabolism
Geun Hyang KimJudith Y Altarejos

Abstract

Leptin alleviates hyperglycemia in rodent models of Type 1 diabetes by activating leptin receptors within the central nervous system. Here we delineate whether non-canonical leptin signaling through the Creb-regulated transcriptional coactivator 1 (Crtc1) contributes to leptin-dependent improvements in diabetic glucose metabolism. We employed mice with a targeted genetic disruption of Crtc1, tracer dilution techniques and neuroanatomical studies to interrogate whether Crtc1 enables leptin to improve glucose metabolism in streptozotocin-induced (STZ) diabetes. Here we show that leptin improves diabetic glucose metabolism through Crtc1-dependent and independent mechanisms. We find that leptin reduces diabetic hyperglycemia, hepatic gluconeogenic gene expression and selectively increases glucose disposal to brown adipose tissue and heart, in STZ-diabetic Crtc1 (WT) mice but not Crtc1 (+/-) mice. By contrast, leptin decreases circulating glucagon levels in both STZ-diabetic Crtc1 (WT) and Crtc1 (+/-) mice. We also demonstrate that leptin promotes Crtc1 nuclear translocation in pro-opiomelanocortin (Pomc) and non-Pomc neurons within the hypothalamic arcuate nucleus (ARC). Accordingly, leptin's ability to induce Pomc gene expression ...Continue Reading

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Mar 11, 2016·Diabetologia·Rachel J PerryGerald I Shulman
Oct 6, 2016·The International Journal of Biochemistry & Cell Biology·Yuanzhong Xu, Qingchun Tong
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May 13, 2021·Nature Communications·Shengjie FanQingchun Tong

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Methods Mentioned

BETA
nuclear translocation
ELISA
PCR
confocal microscopy

Software Mentioned

GraphPad
GraphPad Prism
Aperio
ImageJ
LightCycler 480
GNU Image Manipulation
NIS Elements AR
Nikon Elements
QuantityOne

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