A neural basis for brain leptin action on reducing type 1 diabetic hyperglycemia

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 () and Qingchun Tong ()
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Shengjie Fan: Shanghai University of Traditional Chinese Medicine
Yuanzhong Xu: University of Texas Health Science Center at Houston
Yungang Lu: University of Texas Health Science Center at Houston
Zhiying Jiang: University of Texas Health Science Center at Houston
Hongli Li: University of Texas Health Science Center at Houston
Jessie C. Morrill: University of Texas Health Science Center at Houston
Jing Cai: University of Texas Health Science Center at Houston
Qi Wu: Baylor College of Medicine, One Baylor Plaza
Yong Xu: Baylor College of Medicine, One Baylor Plaza
Mingshan Xue: Department of Neuroscience and Department of Molecular and Human Genetics, Baylor College of Medicine
Benjamin R. Arenkiel: Texas Children’s Hospital
Cheng Huang: Shanghai University of Traditional Chinese Medicine
Qingchun Tong: University of Texas Health Science Center at Houston

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22940-4

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