Neuroscience

Symmetric brain-liver circuits mediate lateralized regulation of hepatic glucose output in mice

Zhonglong Wang
Xiangfei Gong
Li Jiang
Ke Wang
Xinyuan Sun
Yingxi Li
Mengtong Ran
Yanshen Chen
Hongdong Wang
Xuehui Chu
Shun Wang
Junjie Wang
Xiao Zheng author has email address
Haiping Hao author has email address
Hao Xie author has email address

College of Pharmacy, China Pharmaceutical University, Nanjing, China
State Key Laboratory of Natural Medicines, Institute of innovative Drug Discovery and Development, Jiangsu Provincial Key Laboratory of Targetome and Innovative Drugs, China Pharmaceutical University, Nanjing, China
Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China
Department of Pancreatic and Metabolic Surgery, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

https://doi.org/10.7554/eLife.109599.3

Open access
Copyright information

Figures and data

The brain contralaterally projects to the liver.

(A) Representative 3D images of TH-immunostained mouse liver (left), with quantification of sympathetic axon density and lobe volume (right). Scale bar, 3,000 μm. (B) Representative immunofluorescence images of PRV-labeled neurons (EGFP) in the left and right LPGi following PRV injections into the right anterior (left) and median (right) lobes. Scale bars, 200μm (top) and 100 μm (bottom). (C) Quantification of PRV-labeled neurons in left and right LPGi across different hepatic lobes: left lateral, median, right posterior, right anterior, caudate, and porta hepatis (n = 3). (D) Sankey diagram showing projection patterns from left and right LPGi to individual hepatic lobes. (E and F) Representative slices of EGFP⁺ and mRFP⁺ neurons in left (top) and right (bottom) LPGi following PRV-EGFP (right anterior lobe) and PRV-mRFP (median lobe) injections. Proportions of EGFP⁺, mRFP⁺, and co-labeled neurons in left and right LPGi (F, n = 3). Scale bars, 100 μm. Data are expressed as means ± SEM, with individual values shown for all experiments. *p < 0.05, **p < 0.01. Unpaired Student’s t-test for (C).

LPGi stimulation raises blood glucose by driving contralateral, lobe-specific hepatic glycogenolysis.

(A) Scheme for injecting AAV-DIO-hM3Dq or AAV-DIO-mCherry (top). Blood glucose levels following chemogenetic activation of the left, right, or bilateral LPGi, measured at −10, 30, 60, 90, and 120 min (bottom, n = 6). (B and C) Representative immunofluorescence images of pGS (B) and pPYGL (C) expression in the median (top) and right anterior (bottom) lobes after 1 h chemogenetic activation of left, right, or bilateral LPGi, with quantification of relative fluorescence intensity (n = 4-5). Scale bars, 100 μm. (D) Western blot analysis of pPYGL, PYGL, pGS, and GS in median (left) and right anterior (right) lobes after 1 h activation, with densitometric quantification (bottom, n = 3). (E) Plasma concentrations of norepinephrine (NE) (left, n = 5) and epinephrine (EPI) (right, n = 5) following 1 h activation. (F) NE contents in median (left, n = 5) and right anterior (right, n = 5) lobes after 1 h activation. Data are expressed as means ± SEM, with individual values shown for all experiments. *p < 0.05, **p < 0.01, ***p < 0.001; #p < 0.05, ##p < 0.01, ###p < 0.001; $$$p < 0.001. One-way ANOVA with the Tukey test for (A -F).

LPGi maintains glucose balance through compensatory use of ipsilateral hepatic lobes under contralateral lobe impairment.

(A and B) Blood glucose levels in the left- (A, n = 7) or right-sided (B, n = 7) lobes denervated mice. (C) Western blot of TH protein in median and right anterior lobes after denervating left- (top) or right-sided (bottom) lobes (n = 3). (D and E) Representative immunofluorescence images of pGS (top) and pPYGL (bottom) expression in right anterior and median lobes in left- (D) or right-sided (E) lobes denervated mice, with quantification of relative fluorescence intensity (right, n = 5). Scale bars, 100 μm. (F and G) Western blot analysis of pPYGL, PYGL, pGS, and GS proteins in median and right anterior lobes (top) in left- or right-sided lobes denervated mice, with densitometric quantification (bottom, n = 3). (H) NE contents of median and right anterior lobes in left- or right-sided lobes denervated mice (n = 6). (I) Representative immunofluorescence images of c-FOS expression in left and right LPGi in left- or right-sided lobes denervated mice. Scale bars, 100 μm. Data are presented as means ± SEM, with individual values shown for all experiments. *p < 0.05, **p < 0.01, ***p < 0.001. Unpaired Student’s t-test for (A-B, D-H)

Sympathetic projections to the liver decussate at the porta hepatis, progressively formed during development.

(A) Representative 3D images of mice following PRV injection into right- (left) or left-sided (right) lobes. Scale bars, 3000 µm. (B) Representative 3D images of CG-SMG projections to peripheral organs. Scale bar, 3,000 μm. (C) Representative images of sympathetic axons after unilateral CG injection, with quantification of EGFP-labeled axon distribution across hepatic lobes. Scale bars, 100 μm. (D) Representative images of WGA-labeled neurons in left and right CG, with percentages of WGA555⁺, WGA647⁺, and co-labeled neurons. Scale bars, 100 μm. (E) Representative images showing the developmental progression of CG-SMG projections to the liver from postnatal week 0 to week 2. Scale bars, 3,000 µm.

Sign up for email alerts