Diet-induced unresolved metabolic inflammation in fattening Holstein bulls?

High dietary energy and protein intake is needed to gain the maximum growth performance in fattening bulls. However, nutritional surplus is well known to increase obesity, promote insulin insensitivity and generate a low-grade inflammation, detrimental for metabolic health. Thirty Holstein bulls were randomly divided into 2 groups, low energy and protein (LEP) and high energy and protein (HEP) intake, provided from 13^th to 20^th month of life. Life weight, carcass composition and laminitis score were determined. Plasma insulin and glucose concentrations were measured by ELISA and colorimetric assays, respectively. In the liver, muscle and adipose tissue, expression and extent of phosphorylation of insulin signalling proteins were detected by Western Blotting. Sphingolipid metabolome was quantified by a targeted LC-MS based metabolomics approach. Data were analysed by unpaired student`s t-test and by partial least square discriminant analysis, respectively. HEP bulls were obese, and expressed hyperinsulinemia with euglycemia. Clinically, all HEP bulls expressed signs of chronic laminitis. In the liver, protein kinase B (PKB) phosphorylation was decreased and this was associated with higher ceramide (Cer) 16:0 concentrations. Cer 16:0 is well known to diminish insulin signalling by dephosphorylating PKB. In adipose tissue, insulin receptor expression was lower in HEP bulls, and this was associated with higher hexosylceramide concentrations. Hexosylceramides are able to disturb membrane-receptor interactions, thereby reducing the abundance of functional insulin receptors. These major findings indicate that metabolic inflammation induced by dietary surplus induces ceramide accumulation and consequently, disturbs insulin signalling. As insulin insensitivity is known to exacerbate metabolic inflammation, a self-reinforcing cycle was established leading to further increase in ceramide levels and insulin resistance in fattening bulls. Chronic laminitis is a visible signal of this detrimental metabolic situation.