@article{121c793083154b03a1e9330a5aad9f27,
title = "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.",
author = "Sijia He and Jiyoon Ryu and Juanhong Liu and Hairong Luo and Ying Lv and Langlais, {Paul R.} and Jie Wen and Feng Dong and Zhe Sun and Wenjuan Xia and Lynch, {Jane L.} and Ravindranath Duggirala and Nicholson, {Bruce J.} and Mengwei Zang and Yuguang Shi and Fang Zhang and Feng Liu and Juli Bai and Dong, {Lily Q.}",
note = "Funding Information: This work was supported in part by grants from the NIH (DK102965), the American Diabetes Association (1-19-IBS-147), the National Key Research and Development Program of China (2019YFA0801903 and 2018YFC2000100), the National Natural Science Foundation of China (81730022), and the Baptist Health Foundation of San Antonio (2020 Strategic to Mission). We are thankful for the technical support from the Biobanking and Genome Analysis Core, the Core Optical Imaging Facility (supported by UTHSA and NIH-NCI P30 CA54174), the Genome Sequencing Facility (supported by UTHSA, NIH-NCI P30 CA054174, NIH Shared Instrument grant 1S10OD021805-01, and CPRIT Core Facility Award RP160732), and the Nathan Shock Center Aging Animal Models and Longevity Assessment Core (supported by the Nathan Shock Center for Excellence in Basic Biology of Aging grant AG13319), and the Integrated Physiology of Aging Core. We are also thankful for assistance from Novo Nordisk for protein purification and mass spectrometry analysis. We thank Luzhe Sun (UTHSA) for Huh7 control and sh-smad4 cell lines and Christie Bialowas (UTHSA) for providing human serum and adipose samples. Publisher Copyright: {\textcopyright} 2021, American Society for Clinical Investigation.",
year = "2021",
month = dec,
day = "1",
doi = "10.1172/JCI148545",
language = "English (US)",
volume = "131",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "24",
}