A Neural Basis for Brain Leptin Action on Reducing Type 1 Diabetic Hyperglycemia

Authors

Shengjie Fan
Yuanzhong Xu
Yungang Lu
Zhiying Jiang
Hongli Li
Jessie C Morrill
Jing Cai
Qi Wu
Yong Xu
Mingshan Xue
Benjamin R Arenkiel
Cheng Huang
Qingchun Tong

Publication Date

5-11-2021

Journal

Nature Communications

DOI

10.1038/s41467-021-22940-4

PMID

33976218

PMCID

PMC8113586

PubMedCentral® Posted Date

5-11-2021

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes

Keywords

AMP-Activated Protein Kinases, Agouti-Related Protein, Animals, Blood Glucose, Brain, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 1, GABAergic Neurons, Hyperglycemia, Infusions, Intraventricular, Leptin, Male, Mice, Transgenic, Neurons, Receptors, Leptin, Signal Transduction, Diseases of the nervous system, Metabolic disorders

Abstract

Central leptin action rescues type 1 diabetic (T1D) hyperglycemia; however, the underlying mechanism and the identity of mediating neurons remain elusive. Here, we show that leptin receptor (LepR)-expressing neurons in arcuate (LepRArc) are selectively activated in T1D. Activation of LepRArc neurons, Arc GABAergic (GABAArc) neurons, or arcuate AgRP neurons, is able to reverse the leptin’s rescuing effect. Conversely, inhibition of GABAArc neurons, but not AgRP neurons, produces leptin-mimicking rescuing effects. Further, AgRP neuron function is not required for T1D hyperglycemia or leptin’s rescuing effects. Finally, T1D LepRArc neurons show defective nutrient sensing and signs of cellular energy deprivation, which are both restored by leptin, whereas nutrient deprivation reverses the leptin action. Our results identify aberrant activation of LepRArc neurons owing to energy deprivation as the neural basis for T1D hyperglycemia and that leptin action is mediated by inhibiting LepRArc neurons through reversing energy deprivation.