High-fat diets are widely used to study the development of obesity and insulin resistance in rodent models. The fats used in these diets often come from natural sources such as lard, tallow, palm oil or coca butter, which contain fatty acids of varying chain lengths and degrees of saturation. Although different high-fat diets clearly have different effects [1-3], assigning specific effects to individual fatty acids has been challenging. This is particularly relevant and relevant for the differential effects of the saturated long-chain fatty acids (FA) palmitic (C16:0) and stearic (C18:0) representing the most common nutritional long-chain fatty acids stearate

Differences in dietary FA composition are physiologically relevant because the metabolic fate of FAs depends on chain length and saturation. For example, the oxidation efficiency of FA decreases with increasing chain length and saturation. In rats, after oral administration of labeled FA, the oxidation efficiency of saturated FA has been shown to be lauric acid (C12:0) myristic acid (C14:0) palmitic acid (C16:0) stearic acid (C18 :0) [5]. Similar results were found in a human study in which stearic acid was less oxidized after bolus administration compared with lauric acid (13% vs 41% within 9 hours post-dose)[ 6]. Thus, at the cellular level, stearic acid was described to be less susceptible to oxidation by hepatocytes [7]. In addition to their low oxidation efficiency, saturated long-chain FAs are known to directly affect insulin sensitivity in a chain length-dependent manner via a TLR4-dependent pathway [8–10].

In this study, we investigated whether dietary stearate levels in a high-fat diet determine whole-body energy metabolism and tissue-specific insulin sensitivity. For this, mice were fed for 5 weeks a low-stearate diet or two diets enriched in natural or artificial stearate. Whole body metabolism was assessed by indirect calorimetry and body composition was analyzed by dual energy X-ray absorptiometry (DEXA). Tissue-specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp and phosphorylation of key proteins involved in the insulin signaling pathway.