Caloric restriction (CR) is a traditional but scientifically verified approach to promoting health and increasing lifespan. CR exerts its effects through multiple molecular pathways that trigger major metabolic adaptations. It influences key nutrient and energy-sensing pathways including mammalian target of rapamycin, Sirtuin 1, AMP-activated protein kinase, and insulin signaling, ultimately resulting in reductions in basic metabolic rate, inflammation, and oxidative stress, as well as increased autophagy and mitochondrial efficiency. CR shares multiple overlapping pathways with peroxisome proliferator-activated receptors (PPARs), particularly in energy metabolism and inflammation. Consequently, several lines of evidence suggest that PPARs might be indispensable for beneficial outcomes related to CR. In this review, we present the available evidence for the interconnection between CR and PPARs, highlighting their shared pathways and analyzing their interaction. We also discuss the possible contributions of PPARs to the effects of CR on whole organism outcomes.

Heart diseases are the leading cause of death worldwide. Metabolic interventions via ketogenic diets (KDs) have been used for decades to treat epilepsy, and more recently, also diabetes and obesity, as common comorbidities of heart diseases. However, recent reports linked KDs, based on long-chain triglycerides (LCTs), to cardiac fibrosis and a reduction of heart function in rodents. As intervention using medium-chain triglycerides (MCTs) was recently shown to be beneficial in murine cardiac reperfusion injury, the question arises as to what extent the fatty acid (FA)-composition in a KD alters molecular markers of FA-oxidation (FAO) and modulates cardiac fibrotic outcome. The effects of LCT-KD as well as an LCT/MCT mix (8:1 ketogenic ratio) on cardiac tissue integrity and the plasma metabolome were assessed in adult male C57/BL6NRJ mice after eight weeks on the respective diet. Both KDs resulted in increased amount of collagen fibers and cardiac tissue was immunologically indistinguishable between groups. MCT supplementation resulted in i) profound changes in plasma metabolome, ii) reduced hydroxymethylglutaryl-CoA synthase upregulation, and mitofusin 2 downregulation, iii) abrogation of LCT-induced mitochondrial enlargement, and iv) enhanced FAO profile. Contrary to literature, mitochondrial biogenesis was unaffected by KDs. We propose that the observed tissue remodeling is caused by the accumulation of 4-hydroxy-2-nonenal protein adducts, despite an inconspicuous nuclear factor (erythroid-derived 2)-like 2 pathway. We conclude that regardless of the generally favorable effects of MCTs, they cannot inhibit 4-hydroxy-2-nonenal adduct formation and fibrotic tissue formation in this setting. Furthermore, we support the burgeoning concern about the effect of KDs on the cardiac safety profile.

The rate of gut inflammatory diseases is growing in modern society. Previously, we showed that caloric restriction (CR) shapes gut microbiota composition and diminishes the expression of inflammatory factors along the gastrointestinal (GI) tract. The current project aimed to assess whether prominent dietary restrictive approaches, including intermittent fasting (IF), fasting-mimicking diet (FMD), and ketogenic diet (KD) have a similar effect as CR. We sought to verify which of the restrictive dietary approaches is the most potent and if the molecular pathways responsible for the impact of the diets overlap. We characterized the impact of the diets in the context of several dietary restriction-related parameters, including immune status in the GI tract; microbiota and its metabolites; bile acids (BAs); gut morphology; as well as autophagy-, mitochondria-, and energy restriction-related parameters. The effects of the various diets are very similar, particularly between CR, IF, and FMD. The occurrence of a 50 kDa truncated form of occludin, the composition of the microbiota, and BAs distinguished KD from the other diets. Based on the results, we were able to provide a comprehensive picture of the impact of restrictive diets on the gut, indicating that restrictive protocols aimed at improving gut health may be interchangeable.

As we reported previously, caloric restriction (CR) results in an increased concentration of bile acids (BA) in the intestinal mucosa. We now investigated the background of this phenotype, trying to identify nutrition-related factors modulating BA levels. Male mice were submitted to various types of restrictive diets and BA levels and expression of associated factors were measured. We found that BA concentration is increased in the liver of CR mice, which corresponds to reduced expression of the Shp gene and elevated mRNA levels of Cyp27a1, Bal, and Ntcp, as well as CYP7A1 protein and gene expression. Correlation between decreased concentration of BAs in the feces, increased BAs levels in plasma, and elevated gene expression of BAs transporters in the ileum mucosa suggests enhanced BA uptake in the intestine of CR mice. Corresponding to CR upregulation of liver and ileum mucosa, BA concentration was found in animals submitted to other types of prolonged energy-restricting dietary protocols, including intermittent fasting and fasting-mimicking diet. While over-night fasting had negligible impact on BAs levels. Manipulation of macronutrient levels partly affected BA balance. Low-carbohydrate and ketogenic diet increased BAs in the liver but not in the intestine. Carbohydrate restriction stimulates BA synthesis in the liver, but energy restriction is required for the increase in BA levels in the intestine and its uptake.

The capacity of microbiota to produce medium-chain fatty acids (MCFA) and related consequences for the gastrointestinal (GI) tract have never been reported before. We verified the impact of nutrition-related factors on fatty acid (FAs) production and found that caloric restriction decreased levels of most of MCFAs in the mouse cecum, whereas overnight fasting reduced the levels of acetate and butyrate but increased propionate and laurate. A diet high in soluble fibre boosted the production of short-chain fatty acids (SCFA) and caproate whereas a high-cellulose diet did not have an effect or decreased the levels of some of the FAs. Rectal infusion of caprylate resulted in its rapid metabolism for energy production. Repeated 10-day MCFA infusion impacted epididymal white adipose tissue (eWAT) weight and lipid accumulation. Repeated infusion of caprylate rectally tended to increase the concentration of active ghrelin in mice plasma; however, this increase was not statistically significant. In Caco-2 cells, caprylate increased the expression of Fabp2, Pdk4, Tlr3, and Gpr40 genes as well as counteracted TNFα-triggered downregulation of Pparγ, Occludin, and Zonulin mRNA expression. In conclusion, we show that colonic MCFAs can be rapidly utilized as a source of energy or stored as a lipid supply. Further, locally produced caprylate may impact metabolism and inflammatory parameters in the colon.

Our previous study indicated increased levels of taurine-conjugated bile acids (BA) in the intestine content of mice submitted to caloric restriction (CR). In the current project, we found increased levels of free taurine and taurine conjugates, including glutathione (GSH)-taurine, in CR compared to ad libitum fed animals in the mucosa along the intestine but not in the liver. The levels of free GSH were decreased in the intestine of CR compared to ad libitum fed mice. However, the levels of oxidized GSH were not affected and were complemented by the lack of changes in the antioxidative parameters. Glutathione-S transferases (GST) enzymatic activity was increased as was the expression of GST genes along the gastrointestinal tract of CR mice. In the CR intestine, addition of GSH to taurine solution enhanced taurine uptake. Accordingly, the expression of taurine transporter (TauT) was increased in the ileum of CR animals and the levels of free and BA-conjugated taurine were lower in the feces of CR compared to ad libitum fed mice. Fittingly, BA- and GSH-conjugated taurine levels were increased in the plasma of CR mice, however, free taurine remained unaffected. We conclude that CR-triggered production and release of taurine-conjugated BA in the intestine results in increased levels of free taurine what stimulates GST to conjugate and enhance uptake of taurine from the intestine.