Kupffer cells ameliorate hepatic insulin resistance induced by high-fat diet rich in monounsaturated fatty acids: the evidence for the involvement of alternatively activated macrophages

Male Wistar rats were fed either standard (SD) or high-fat (HF) diet for 4 weeks. Half of the animals were subjected to the acute GdCl3 treatment 24 and 72 hrs prior to the end of the experiment in order to induce the reduction of KCs population. We determined the effect of HF diet on activation status of liver macrophages and on the changes in hepatic insulin sensitivity and triacylglycerol metabolism imposed by acute KCs depletion by GdCl3.We found that a HF diet rich in MUFA itself triggers an alternative but not the classical activation program in KCs. In a steatotic, but not in normal liver, a reduction of the KCs population was associated with a decrease of alternative activation and with a shift towards the expression of pro-inflammatory activation markers, with the increased autophagy, elevated lysosomal lipolysis, increased formation of DAG, PKCε activation and marked exacerbation of HF diet-induced hepatic insulin resistance.We propose that in the presence of a high MUFA content the population of alternatively activated resident liver macrophages may mediate beneficial effects on liver insulin sensitivity and alleviate the metabolic disturbances imposed by HF diet feeding and steatosis. Our data indicate that macrophage polarization towards an alternative state might be a useful strategy for treating type 2 diabetes.Obesity and type 2 diabetes have reached epidemic proportions in most of the Western world. Both conditions are strongly associated with non-alcoholic fatty liver disease (NAFLD) [1]. Obesity was first recognized as a chronic low-grade inflammatory condition of adipose tissue more than a decade ago [2]. Both liver and adipose tissue possess a specific macrophage subpopulation -"resident macrophages"- that undergo local activation in response to various stimuli and express distinct patterns of surface markers, chemokines and cytokines [3]. Depending on the triggering stimuli and genetic background, macrophages can undergo either a "classical" (T