Positive Adipose Liver Crosstalk Protects Adipose MTP Knockout Mice from Hepatic Steatosis on an Obesogenic Diet

Introduction: Our previous study demonstrated that adipocyte MTP regulates intracellular lipolysis by inhibiting ATGL activity. Adipose-specific MTP knockout mice (A- Mttp -/- ) had smaller adipocytes and showed increased thermogenesis and gained less weight on an obesogenic diet. They also exhibited moderately high plasma triglyceride levels and less hepatic steatosis compared to wild-type counterparts. In this study, we have elucidated the mechanism behind less hepatic lipid accumulation and moderately high plasma TG in A- Mttp -/- mice. Methods: We characterized lipoproteins and studied hepatic ApoB production. We have analyzed adipose-liver crosstalk using two strategies 1) lipidomics of adipose tissue, plasma, and liver. 2) adipokine profiling. Further, we have used western blotting and qRT-PCR to check signaling and gene expression. Results: Plasma lipid profiling revealed increased TG content in the VLDL and LDL fraction of A- Mttp -/- mice compared to Mttp f/f mice. Additionally, A- Mttp -/- mice showed significantly increased hepatic triglyceride production compared to the wild type. Lipidomic analysis revealed the movement of fatty acids from adipose tissue to the liver, resulting in significantly higher amounts of oleate, palmitate, linoleate, and stearate in the liver of A- Mttp -/- mice compared to Mttp f/f mice. A- Mttp -/- mice liver also showed significantly increased expression of genes involved in fatty acid uptake and utilization such as Cd36 , Mcad , Fatp2 , and Cpt1a compared to Mttp f/f mice. Further adipokine profiling showed a significantly higher amount of adiponectin and decreased amount of proinflammatory cytokines such as leptin in the plasma of A- Mttp -/- mice compared to Mttp f/f mice. We also found decreased ceramide levels and significantly increased phosphorylation of AMPK in the liver of A- Mttp -/- mice compared to Mttp f/f mice. Conclusion: We conclude that increased availability of substrate for TG production might contribute to increased ApoB secretion by the liver of A- Mttp -/- mice. In addition, positive cytokine profile and increased adiponectin signaling in the liver of A- Mttp -/- mice protects it from hepatic steatosis.