Level of dietary energy and 2,4-thiazolidinedione alter molecular and systemic biomarkers of inflammation and liver function in Holstein cows

Afshin Hosseini, Mustafa Salman, Zheng Zhou, James K. Drackley, Erminio Trevisi, Juan J. Loor

The objective of the study was to evaluate the effect of overfeeding a moderate energy diet and a 2,4-thiazolidinedione (TZD) injection on blood and hepatic tissue biomarkers of lipid metabolism, oxidative stress, and inflammation as it relates to insulin sensitivity. Fourteen dry non-pregnant cows were fed a control (CON) diet to meet 100% of NRC requirements for 3 wk, after which half of the cows were assigned to a moderate-energy diet (OVE) and half of the cows continued on CON for 6 wk. All cows received an intravenous injection of 4 mg TZD/kg of body weight (BW) daily from 2 wk after initiation of dietary treatments and for 2 additional week. Compared with CON cows and before TZD treatment, the OVE cows had lower concentration of total protein, urea and albumin over time. The concentration of cholesterol and tocopherol was greater after 2 wk of TZD regardless of diet. Before and after TZD, the OVE cows had greater concentrations of AST/GOT, while concentrations of paraoxonase, total protein, globulin, myeloperoxidase, and haptoglobin were lower compared with CON cows. Regardless of diet, TZD administration increased the concentration of ceruloplasmin, ROMt, cholesterol, tocopherol, total protein, globulin, myeloperoxidase and beta-carotene. In contrast, the concentration of haptoglobin decreased at the end of TZD injection regardless of diet. Prior to TZD injection, the mRNA expression of PC, ANGPTL4, FGF21, INSR, ACOX1, and PPARD in liver of OVE cows was lower compared with CON cows. In contrast, the expression of HMGCS2 was greater in OVE compared with CON cows. After 1 wk of TZD administration the expression of IRS1 decreased regardless of diet; whereas, expression of INSR increased after 2 wk of TZD injection. Cows fed OVE had lower overall expression of TNF, INSR, PC, ACOX1, FGF21, and PPARD but greater HMGCS2 expression. These differences were most evident before and after 1 wk of TZD injection, and by 2 wk of TZD differences in expression for most genes disappeared. Based on molecular and blood data, administration of TZD enhanced some aspects of insulin sensitivity while causing contradictory results in terms of inflammation and oxidative stress. The bovine liver is TZD-responsive and level of dietary energy can modify the effects of TZD. Because insulin sensitizers have been proposed as useful tools to manage dairy cows during the transition period, further studies are required to investigate the potential hepatotoxicity effect of TZD (or similar compounds) in dairy cattle.