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
Affiliations
Tong Guo
Center for Human Nutrition, University of Texas Southwestern Medical Center, 5300 Harry Hines Boulevard, Dallas, TX, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Arun Gupta
Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Jinhai Yu
Center for Human Nutrition, University of Texas Southwestern Medical Center, 5300 Harry Hines Boulevard, Dallas, TX, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA
Jorge Z. Granados
Center for Human Nutrition, University of Texas Southwestern Medical Center, 5300 Harry Hines Boulevard, Dallas, TX, USA
Aakash Y. Gandhi
Center for Human Nutrition, University of Texas Southwestern Medical Center, 5300 Harry Hines Boulevard, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA
Bret M. Evers
Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA
Puneeth Iyengar
Center for Human Nutrition, University of Texas Southwestern Medical Center, 5300 Harry Hines Boulevard, Dallas, TX, USA; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Corresponding author
Rodney E. Infante
Center for Human Nutrition, University of Texas Southwestern Medical Center, 5300 Harry Hines Boulevard, Dallas, TX, USA; Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA; Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA; Corresponding author
Summary: 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;LIFRfl/fl). Differentiated adipocytes derived from this model blocked LIF-induced triacylglycerol lipolysis. Adipoq-Cre;LIFRfl/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;STAT3fl/fl model that showed similar findings when fed a HFD as Adipoq-Cre;LIFRfl/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.
