LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance
Sijia He, … , Juli Bai, Lily Q. Dong
Sijia He, … , Juli Bai, Lily Q. Dong
Published November 2, 2021
Citation Information: J Clin Invest. 2021;131(24):e148545. https://doi.org/10.1172/JCI148545.
View: Text | PDF
Research Article Endocrinology Metabolism

LRG1 is an adipokine that mediates obesity-induced hepatosteatosis and insulin resistance

Abstract

Dysregulation in adipokine biosynthesis and function contributes to obesity-induced metabolic diseases. However, the identities and functions of many of the obesity-induced secretory molecules remain unknown. Here, we report the identification of leucine-rich alpha-2-glycoprotein 1 (LRG1) as an obesity-associated adipokine that exacerbates high fat diet–induced hepatosteatosis and insulin resistance. Serum levels of LRG1 were markedly elevated in obese humans and mice compared with their respective controls. LRG1 deficiency in mice greatly alleviated diet-induced hepatosteatosis, obesity, and insulin resistance. Mechanistically, LRG1 bound with high selectivity to the liver and promoted hepatosteatosis by increasing de novo lipogenesis and suppressing fatty acid β-oxidation. LRG1 also inhibited hepatic insulin signaling by downregulating insulin receptor substrates 1 and 2. Our study identified LRG1 as a key molecule that mediates the crosstalk between adipocytes and hepatocytes in diet-induced hepatosteatosis and insulin resistance. Suppressing LRG1 expression and function may be a promising strategy for the treatment of obesity-related metabolic diseases.

Authors

Sijia He, Jiyoon Ryu, Juanhong Liu, Hairong Luo, Ying Lv, Paul R. Langlais, Jie Wen, Feng Dong, Zhe Sun, Wenjuan Xia, Jane L. Lynch, Ravindranath Duggirala, Bruce J. Nicholson, Mengwei Zang, Yuguang Shi, Fang Zhang, Feng Liu, Juli Bai, Lily Q. Dong

×

Figure 5

LRG1 promotes insulin resistance through downregulation of IRS expression in hepatocytes.

Options: View larger image (or click on image) Download as PowerPoint
LRG1 promotes insulin resistance through downregulation of IRS expressio...
(A) Dosage effect of LRG1 protein treatment on insulin signaling in hepatocytes. Primary hepatocytes from C57BL/6J mice were pretreated with different doses of LRG1 for 16 hours before treated with 10 nM insulin for 5 minutes. (B) Time effect of LRG1 protein treatment on insulin signaling in mouse primary hepatocytes. Cells were pretreated with LRG1 at 20 μg/mL for indicated lengths of time prior to stimulation with 10 nM insulin for 5 minutes. (C) Protein and/or its phosphorylation levels of insulin signaling components in primary hepatocytes treated with or without LRG1 (20 μg/mL, 16 hours) prior exposure to insulin (10 nM, 5 minutes) (n = 3/treatment group). (D) IRS1/2 protein levels in the liver tissue of WT and Lrg1KO mice after fed with HFD for 16 weeks (n = 4/group). (E) qPCR evaluation of G6Pase mRNA levels in hepatocytes treated with or without LRG1 (20 μg/mL) for 1 hour (n = 3/group). (F) The effect of LRG1 (20 μg/mL, 16 hours) on insulin-induced suppression of gluconeogenesis in mouse primary hepatocytes (n = 3/treatment group). Primary hepatocytes from C57BL/6J mice were treated with the reagents as indicated, the glucose release was then measured by colorimetric method. All cell experiments were independently repeated for 3 times. Data represent mean ± SEM. Unpaired 2-tailed t test for (C–E). One-way ANOVA followed by Tukey’s test for F. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001.