Short Term Palmitate Supply Impairs Intestinal Insulin Signaling via Ceramide Production

Abstract

The worldwide prevalence of metabolic diseases is increasing, and there are global recommendations to limit consumption of certain nutrients, especially saturated lipids. Insulin resistance, a common trait occurring in obesity and type 2 diabetes, is associated with intestinal lipoprotein overproduction. However, the mechanisms by which the intestine develops insulin resistance in response to lipid overload remain unknown. Here, we show that insulin inhibits triglyceride secretion and intestinal microsomal triglyceride transfer protein expression in vivo in healthy mice force-fed monounsaturated fatty acid-rich olive oil but not in mice force-fed saturated fatty acid-rich palm oil. Moreover, when mouse intestine and human Caco-2/TC7 enterocytes were treated with the saturated fatty acid, palmitic acid, the insulinsignaling pathway was impaired. We show that palmitic acid or palm oil increases ceramide production in intestinal cells and that treatment with a ceramide analogue partially reproduces the effects of palmitic acid on insulin signaling. In Caco-2/TC7 enterocytes, ceramide effects on insulin-dependent AKT phosphorylation are mediated by protein kinase C but not by protein phosphatase 2A. Finally, inhibiting de novo ceramide synthesis improves the response of palmitic acid-treated Caco-2/TC7 enterocytes to insulin. These results demonstrate that a palmitic acid-ceramide pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure.The worldwide obesity epidemic has stimulated numerous research efforts to identify factors that affect energy balance. As compared with the liver, pancreas, muscle, or adipose tissues, the intestine has received little attention with regard to its potential role in the onset of metabolic disorders. Nevertheless, the intestine could also contribute to the development of metabolic disease, especially through its role in postprandial lipemia.The increased amplitude and duration of the postprandial peak of circulating triglyceride-rich lipoproteins (TRL) 5 are known risk factors for atherosclerosis and cardiovascular diseases (1, 2). Postprandial hypertriglyceridemia can be due to impaired TRL catabolism, and/or lipoprotein remnant uptake, and may also result from intestinal TRL overproduction (3). Thus, investigating intestinal lipoprotein secretion might help to understand aberrant postprandial lipemia (4).The intestine ensures the transport of alimentary fat, which is the most calorie-dense nutrient. Enterocytes produce intestinal TRLs (chylomicrons) along a multistep pathway, which includes long chain fatty acid uptake, triglyceride synthesis in the endoplasmic reticulum, and assembly with apolipoproteins (apo) such as apoB48. Chylomicrons are then secreted into the lymph and ultimately into the blood. Overproduction of intestinal TRL may be an important contributor of both fasting and postprandial dyslipidemia (3, 5). Microsomal triglyceride transfer protein (MTP) transports neutral lipids (6) and plays a cen...

High Fat Diets Composed of Palm Stearin and Olive Oil Equally Exacerbate Liver Inflammatory Damage and Metabolic Stress in Mice

“…It was suggested that a mechanism that can differentiate between the metabolic effect of MUFA and saturated fatty acids is related to the palmitic acid‐ceramide pathway. This pathway accounts for impaired intestinal insulin sensitivity, which occurs within several hours following initial lipid exposure . However, this can apply to short‐term supplementation.…”

Obesity-induced cardiac lipid accumulation in adult mice is modulated by G protein-coupled receptor kinase 2 levels

“…Inappropriate triglyceride deposition into cytoplasmic lipid droplets enlarges the intracellular pool of fatty acyl-CoA thereby providing substrate for oxidative and non-oxidative (e.g. ceramide synthesis [10, 11]) metabolic pathways leading to oxidative stress, cellular dysfunction and apoptosis and insulin resistance [43]. However, such packaging of lipid excess into lipid droplets can also be regarded as an adaptive response of the tissue to accommodate an excessive energy supply while keeping low concentrations of lipotoxic intermediates [44].…”

“…The ectopic presence of triglycerides and lipid metabolites such as ceramides has been related to lipotoxicity and cardiomyocyte apoptosis [9]. Interestingly, a palmitic acid-ceramide pathway accounts for impaired insulin sensitivity [10], whereas ceramide inhibition has been suggested to be an effective deterrent to heart disease risk in conditions like hyperinsulinemia [11]. In fact, a positive correlation between cardiac lipid accumulation and cardiac dysfunction has been established giving rise to the term lipotoxic cardiomyopathy.…”

Describing the fecal metabolome in cryogenically collected samples from healthy participants

“…54 Ceramides are found in large quantities in cell membranes and contribute to cellular signaling mechanisms, particularly cell death, partially reproducing the effect of palmitic acid on insulin signaling. 55 Triacylglycerols and diacylglycerols are usually thought of as energy metabolites, although they can also be signaling molecules and have long been implicated in the occurrence of metabolic syndrome. 56…”