(P31-003-23) Albumin Knockout Mice With Diet-Induced Obesity Exhibit Reduced Hepatic Steatosis and Improved Glucose Metabolism

Objectives: To improve understanding of the potential metabolic health benefits of reducing plasma free fatty acids (FFA), we tested whether albumin knockout (Alb^−/−) mice challenged with diet-induced obesity would exhibit reduced hepatic lipid accumulation and improved glucoregulation as compared to obese wild-type (WT) mice.

Methods: Male Alb^−/− and WT controls were studied on low-fat diet (LFD) and high-fat diet (HFD) for eight weeks. Body composition was tested by magnetic resonance. Glucose metabolism was studied by oral glucose tolerance testing and insulin tolerance testing. Substrate oxidation was measured by indirect calorimetry over 24 hours in metabolic cages. Plasma and tissues were collected after a 4-6 hour fast.  Hepatic ceramide, diacylglycerol, and cholesteryl ester were measured by liquid chromatography/ mass spectrometry (LC/MS).  Plasma FFA and hepatic triacylglycerol concentrations were measured by colorimetric assays. Hepatic steatosis was measured by Oil Red O staining. Gene and protein expression were measured in liver and adipose tissue, and LC/MS-based proteomics analysis of plasma was carried out. Statistical analyses were done by ANOVA with p< 0.05 indicating significance.

Results: Alb^−/− mice exhibited similar body composition as WT on each diet. Alb^−/− mice were protected from various comorbidities of diet-induced obesity. Compared to WT mice on a HFD, Alb^−/− exhibited lower plasma FFA, lower blood glucose during glucose tolerance and insulin tolerance tests, and lower hepatic steatosis and inflammation. Alb^−/− mice on HFD also exhibited higher expression than WT for peroxisome proliferator-activated receptor α and its downstream target acyl-CoA dehydrogenase long-chain in liver and adipose tissue. Alb^−/− mice also displayed higher adipose tissue glucose transporter-4 and adiponectin expression, as compared with WT on the same diets.

Conclusions: Interrupting albumin’s FFA transport function may be a beneficial approach for limiting the development of hepatic lipid accumulation and the dysregulated glucose metabolism that commonly occur in obesity.

Funding Sources: The work was supported by the NIH (NIDDK), a Pilot and Feasibility Grant from the NIH-funded Center for Diabetes and Metabolic Diseases at Indiana University School of Medicine, as well as by support from the McKinley Educational Initiative.