Long-term caloric restriction up-regulates PPAR gamma co-activator 1 alpha (PGC-1<img src='/image/spc_char/alpha.gif' border=0> ) expression in mice

272-277The peroxisome proliferator-activated receptor (PPAR) gamma co-activator 1 alpha (PGC-1 ), a signal-sensing transcriptional co-activator in association with many nuclear receptors regulates various genes that control energy balance in animals. In this study, the effect of long-term caloric restriction (CR) (alternate days of fasting for 3 months) on the expression of PGC-1 protein in various tissues was investigated in mice. Western blot analyses showed positive immunoreactive PGC-1 (~92 kDa) signal from various tissues. Heart, kidney and skeletal muscles expressed significant levels of PGC-1 , while a comparatively lower level was detected in the liver, small intestine and brain. The expression of PGC-1 was the highest and lowest in the heart and liver respectively. CR mice exhibited a significant increase in PGC-1a level in the heart (5.13-fold), kidney (3.57-fold), skeletal muscle (3.02-fold), liver (2.60-fold), small intestine (2.45-fold) and brain (2.05-fold), compared to normal (ad libitum) fed. The elevation in PGC-1 level, especially in highly oxidative tissues such as heart, kidney and skeletal muscle of CR mice might synergistically up-regulate genes that require PGC-1 co-activation. Taken together, the up-regulation of PGC-1 expression might potentially support optimal energy metabolism and biochemical adaptation, necessary for maintaining energy homeostasis during long-term CR

Gut Microbiota and Host Nuclear Receptors Signalling

Systemic homeostasis in animals is maintained by a network of complex signalling pathways involving several kinds of endogenous molecules/metabolites. Over the years, the role of microbiota present in the digestive tract in animal physiology has been under focus and path-breaking findings have been reported. It seems that the gut microbiota has an influence in perhaps almost all the physiological functions, including the central nervous system in animals. The means by which the microbiota impinges control on the host system biology is manifold and complex. However, one of the mechanisms involve microbiota-derived metabolites that functions as ligands to modulate host tissue gene expression via the nuclear receptors (NRs), which is a novel way of exerting control over the host physiology. Few of the host NRs, such as the pregnane X receptor (PXR), farnesoid X receptor (FXR) and peroxisome-proliferator activated receptors (PPARs) gene transcriptional activities have been demonstrated to be modulated by the binding of microbial-secreted metabolites acting as ligands. Such interactions control vital functions in the host such as intestinal epithelial barrier protection, immune tolerance and anti-inflammatory responses. In this article, recent important findings in understanding gut microbiota-derived metabolites and select host NRs signalling will be briefly reviewed

Human microbial metabolite mimicry as a strategy to expand the chemical space of potential drugs.

he concept of small-molecule mimicry even of weak microbial metabolites present in rodents and humans, as a means to expand drug repertoires, is new. Hitherto, there are few proof-of-concept papers demonstrating utility of this concept. More recently, papers demonstrating mimicry of intestinal microbial metabolites could expand the drug repertoire for diseases such as inflammatory bowel disease (IBD). We opine that, as more functional metabolite-receptor pairings are discovered, small-molecule metabolite mimicry could be a significant effort in drug discovery

Xenobiotic Receptor-Mediated Regulation of Intestinal Barrier Function and Innate Immunity

The molecular basis for the regulation of the intestinal barrier is a very fertile research area. A growing body of knowledge supports the targeting of various components of intestinal barrier function as means to treat a variety of diseases, including the inflammatory bowel diseases. Herein, we will summarize the current state of knowledge of key xenobiotic receptor regulators of barrier function, highlighting recent advances, such that the field and its future are succinctly reviewed. We posit that these receptors confer an additional dimension of host-microbe interaction in the gut, by sensing and responding to metabolites released from the symbiotic microbiota, in innate immunity and also in host drug metabolism. The scientific evidence for involvement of the receptors and its molecular basis for the control of barrier function and innate immunity regulation would serve as a rationale towards development of non-toxic probes and ligands as drugs

Targeting the pregnane X receptor using microbial metabolite mimicry

The human PXR (pregnane X receptor), a master regulator of drug metabolism, has essential roles in intestinal homeostasis and abrogating inflammation. Existing PXR ligands have substantial offtarget toxicity. Based on prior work that established microbial (indole) metabolites as PXR ligands, we proposed microbial metabolite mimicry as a novel strategy for drug discovery that allows exploiting previously unexplored parts of chemical space. Here, we report functionalized indole derivatives as first-in-class non-cytotoxic PXR agonists as a proof of concept for microbial metabolite mimicry. The lead compound, FKK6 (Felix Kopp Kortagere 6), binds directly to PXR protein in solution, induces PXRspecific target gene expression in cells, human organoids, and mice. FKK6 significantly represses pro-inflammatory cytokine production cells and abrogates inflammation in mice expressing the human PXR gene. The development of FKK6 demonstrates for the first time that microbial metabolite mimicry is a viable strategy for drug discovery and opens the door to underexploited regions of chemical space