LIFR-α-dependent adipocyte signaling in obesity limits adipose expansion contributing to fatty liver disease

Tong Guo; Arun Gupta; Jinhai Yu; Jorge Z Granados; Aakash Y Gandhi; Bret M Evers; Puneeth Iyengar; Rodney E Infante

doi:10.1016/j.isci.2021.102227

LIFR-α-dependent adipocyte signaling in obesity limits adipose expansion contributing to fatty liver disease

iScience. 2021 Feb 24;24(3):102227. doi: 10.1016/j.isci.2021.102227. eCollection 2021 Mar 19.

Authors

Tong Guo^{1

2}, Arun Gupta³, Jinhai Yu^{1

2}, Jorge Z Granados¹, Aakash Y Gandhi^{1

4}, Bret M Evers⁵, Puneeth Iyengar^{1

3

4}, Rodney E Infante^{1

2

4

6}

Affiliations

¹ Center for Human Nutrition, University of Texas Southwestern Medical Center, 5300 Harry Hines Boulevard, Dallas, TX, USA.
² Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
³ Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁴ Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁵ Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
⁶ Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.

Abstract

The role of chronic adipose inflammation in diet-induced obesity (DIO) and its sequelae including fatty liver disease remains unclear. Leukemia inhibitory factor (LIF) induces JAK-dependent adipocyte lipolysis and altered adipo/cytokine expression, suppressing in vivo adipose expansion in normal and obese mouse models. To characterize LIF receptor (LIFR-α)-dependent cytokine signaling in DIO, we created an adipocyte-specific LIFR knockout mouse model (Adipoq-Cre;LIFR ^fl/fl ). Differentiated adipocytes derived from this model blocked LIF-induced triacylglycerol lipolysis. Adipoq-Cre;LIFR ^fl/fl mice on a high-fat diet (HFD) displayed reduced adipose STAT3 activation, 50% expansion in adipose, 20% body weight increase, and a 75% reduction in total hepatic triacylglycerides compared with controls. To demonstrate that LIFR-α signals adipocytes through STAT3, we also created an Adipoq-Cre;STAT3 ^fl/fl model that showed similar findings when fed a HFD as Adipoq-Cre;LIFR ^fl/fl mice. These findings establish the importance of obesity-associated LIFR-α/JAK/STAT3 inflammatory signaling in adipocytes, blocking further adipose expansion in DIO contributing to ectopic liver triacylglyceride accumulation.

Keywords: Animal Physiology; Biological Sciences; Cell Biology; Cellular Physiology; Endocrinology.