P15 – Endoplasmic Reticulum Stress in Adipose Tissue Stimulates Lipolysis In Vivo

Author(s):
Elena Bogdanovic, Nicole Kraus, Abdikarim Abdullahi, Marc Jeschke, Sunnybrook Health Sciences Centre

Background: Endoplasmic reticulum stress (ER stress) or ER dysfunction affects numerous cellular processes and has been implicated as a contributing factor in several pathophysiological conditions. The antibiotic tunicamycin induces ER stress in a variety of cell types in vitro and has been used as a tool to induce ER stress in vivo. In mice, tunicamycin induces a robust ER stress response within the liver and kidney, accompanied by lipid accumulation and cell apoptosis. Recently, ER stress in adipocytes has been shown to stimulate lipolysis in vitro.

Hypothesis: We hypothesized that hepatic ER stress and the development of fatty livers induced by tunicamycin was due to increased lipolysis from adipose tissue.

Methods: Male Balb/c mice were injected intraperitoneally with tunicamycin. The liver and adipose tissue was dissected at various times post injection and ER stress was evaluated by Western blotting and quantitative real-time PCR. Plasma glycerol levels were determined using a colourimetric assay.

Results: We examined whether tunicamycin stimulated ER stress in adipose tissue in vivo and whether ER stress induced lipolysis was associated with fatty infiltration of the liver and hepatic ER stress. We show that tunicamycin administration in male mice rapidly induced an ER stress response in adipose tissue that correlated with increased lipolysis, fatty infiltration of the liver, increases in liver density and hepatic ER stress. The stimulation of lipolysis by tunicamycin was rapid, detectable after 2 h both in vitro and in vivo and did not involve increased phosphorylation of hormone sensitive lipase (HSL). Prolonged (18-21 h) incubation of primary adipocytes with tunicamycin induced widespread changes in protein expression such as decreased phosphorylation of HSL and reduced expression of perilipin.

Conclusions: Our results highlight a possible role for ER stress induced lipolysis in adipose tissue as an underlying mechanism leading to increases in serum free fatty acids (FFAs), fatty infiltration of the liver, hepatic ER stress and hepatic apoptosis.