Gut microbiota-mediated metabolic dysregulation in type 2 diabetes and metabolic syndrome: emerging therapeutic targets beyond glycaemic control.

Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity

Bile acids play important roles in the regulation of lipid, glucose, and energy homeostasis. Recent studies suggest that glucose regulates gene transcription in the liver. The aim of this study was to investigate the potential role of glucose in regulation of bile acid synthesis in human hepatocytes. High glucose stimulated bile acid synthesis and induced mRNA expression of cholesterol 7alpha-hydroxylase (CYP7A1), the key regulatory gene in bile acid synthesis. Activation of an AMP-activated protein kinase (AMPK) decreased CYP7A1 mRNA, hepatocyte nuclear factor 4alpha (HNF4alpha) protein, and binding to CYP7A1 chromatin. Glucose increased ATP levels to inhibit AMPK and induce HNF4alpha to stimulate CYP7A1 gene transcription. Furthermore, glucose increased histone acetylation and decreased H3K9 di- and tri-methylation in the CYP7A1 chromatin. Knockdown of ATP-citrate lyase, which converts citrate to acetyl-CoA, decreased histone acetylation and attenuated glucose induction of CYP7A1 mRNA expression. These results suggest that glucose signaling also induces CYP7A1 gene transcription by epigenetic regulation of the histone acetylation status. This study uncovers a novel link between hepatic glucose metabolism and bile acid synthesis. Glucose induction of bile acid synthesis may have an important implication in metabolic control of glucose, lipid, and energy homeostasis under normal and diabetic conditions.

Breast cancer (BC) is associated with type 2 diabetes mellitus (T2DM) and obesity. Glucagon-like peptide (GLP)-1 regulates post-prandial insulin secretion, satiety, and gastric emptying. Several GLP-1 analogs have been FDA-approved for the treatment of T2DM and obesity. Moreover, GLP-1 regulates various metabolic activities across different tissues by activating metabolic signaling pathways like adenosine monophosphate (AMP) activated protein kinase (AMPK), and AKT. Rewiring metabolic pathways is a recognized hallmark of cancer, regulated by several cancer-related pathways, including AKT and AMPK. As GLP-1 regulates AKT and AMPK, we hypothesized that it alters BC cells' metabolism, thus inhibiting proliferation. The effect of the GLP-1 analogs exendin-4 (Ex4) and liraglutide on viability, AMPK signaling and metabolism of BC cell lines were assessed. Viability of BC cells was evaluated using colony formation and MTT/XTT assays. Activation of AMPK and related signaling effects were evaluated using western blot. Metabolism effects were measured for glucose, lactate and ATP. Exendin-4 and liraglutide activated AMPK in a cAMP-dependent manner. Blocking Ex4-induced activation of AMPK by inhibition of AMPK restored cell viability. Interestingly, Ex4 and liraglutide reduced the levels of glycolytic metabolites and decreased ATP production, suggesting that GLP-1 analogs impair glycolysis. Notably, inhibiting AMPK reversed the decline in ATP levels, highlighting the role of AMPK in this process. These results establish a novel signaling pathway for GLP-1 in BC cells through cAMP and AMPK modulation affecting proliferation and metabolism. This study suggests that GLP-1 analogs should be considered for diabetic patients with BC.

AMP-Activated Protein Kinase Signaling Protects Oligodendrocytes that Restore Central Nervous System Functions in an Experimental Autoimmune Encephalomyelitis Model

A tea catechin, epigallocatechin-3-gallate, is a unique modulator of the farnesoid X receptor

Targeting Farnesoid X Receptor in Hepatic and Biliary Inflammatory Diseases

Structure-guided modification of isoxazole-type FXR agonists: Identification of a potent and orally bioavailable FXR modulator

ABSTRACTIntroduction: Farnesoid X receptor (FXR), a nuclear receptor mainly expressed in enterohepatic tissues, is a master for bile acid, lipid and glucose homeostasis. Additionally, it acts as a cell protector with unclear mechanism but may be implicated in combating against inflammation, fibrosis and cancers. FXR is thus accepted as a promising target particularly for the enterohepatic diseases, and numerous FXR modulators have been patented and developed.Areas covered: This review provides an update on the development of FXR modulators for enterohepatic diseases and offers an in-depth perspective on new strategies for the development of novel FXR modulators.Expert opinion: Despite the development of numerous FXR modulators, which culminated in the successful launch of obeticholic acid (OCA), it remains a matter of debate on how the function of FXR should be exploited for therapeutic purposes. The improvement for obesity achieved by either FXR agonists or antagonists is still in confusion. Whether the side effect of pruritus induced by OCA could be exempted for non-steroidal FXR agonists needs further validation. Apart from the development of conventional FXR ligands, emerging evidence support that restoration of FXR protein level may represent a new strategy in targeting FXR for enterohepatic and metabolic diseases.

Liver X Receptor and Farnesoid X Receptor as Therapeutic Targets

The role of AMPK signaling pathway in the pathogenesis of type 2 diabetes mellitus with its complications and related metabolic disorders

Long-term abnormal levels of glycolipid metabolism damage the organs, leading to a gradual decline in organ functions. In treating glycolipid metabolism disorders, the gut-liver axis plays a key role and has become a hot research topic. It is worth noting that traditional Chinese medicine(TCM) and its active ingredients have been proven to have strong anti-inflammatory and immune regulatory functions in its long history and modern research. Therefore, this paper aims to illustrate the research progress of TCM in effectively improving glycolipid metabolism disorders and alleviating metabolic disease symptoms by regulating the gut-liver axis adenosine monophosphate-activated protein kinase(AMPK)/farnesoid X receptor(FXR)/Toll-like receptor 4(TLR4) signal network. Specifically, TCM and its derivatives can improve intestinal barrier function and flora environment, inhibit the production and translocation of harmful secretions in the intestine, and promote the secretion of short-chain fatty acids(SCFAs) and ceramides, thus regulating key signal molecules AMPK, FXR, and TLR4 of glycolipid metabolism through the gut-liver axis structure. According to research, TCM active ingredients function in two ways. On one hand, ingredients such as baicalin, curcumin, and ginsenosides can regulate the FXR expression and affect the secretion and metabolism of bile acids(BAs) to balance glucose and lipid levels. On the other hand, the ingredients can activate AMPK, inhibit TLR4, and control the secretion of proteins related to lipid and glucose synthesis, such as sterol regulatory element binding protein 1c(SREBP-1c), and peroxisome proliferator activated receptor(PPAR), as well as inflammatory factors to regulate glycolipid metabolism. Among them, the activation of AMPK can downregulate the TLR4 expression, and FXR is also subject to the negative feedback effect of AMPK. For the first time, this article discussed that TCM can coordinate the glycolipid metabolism regulation based on the gut-liver axis through the signal network of AMPK, FXR, and TLR4, thereby effectively treating glycolipid metabolism disorders. With unique clinical treatment advantages of small side effects, high safety, and "multiple targets coordinated treatment", TCM is favorable to glycolipid metabolism disorders, providing a new direction to develop new drugs for glycolipid metabolism disorders.

The hypothesis that AMP-activated protein kinase (AMPK) acts as the ‘metabolic governor’ has deservedly received considerable attention (Winder, 2001). Studies defining the signalling pathway are elegant, the level of effort almost Olympian in nature, and the implications mighty, in terms of both the science and the potential for clinical application. However, while new and exciting, the notion that a single pathway acts as a metabolic governor in working mammalian muscle overlooks a lot of what is known about metabolic regulation. Now, with the results of McConell et al. (2005) in this issue of The Journal of Physiology, it is time to reassess the relevance of the AMPK signalling pathway for the regulation of metabolism in working human muscle. The notion that AMPK or any other component of the signalling pathway acts as a metabolic governor begs for consideration of a definition of ‘metabolism’. Typically, metabolism is described as ‘the sum of all processes in a living organism’, and because these processes involve heat production, ‘metabolic rate’ is commonly defined as ‘the rate of heat production’ (Brooks et al. 2004). Proponents of the hypothesis of AMPK as a metabolic governor overlooked basic definitions of ‘metabolism’ and ‘metabolic rate’ and neither proposed nor provided data to show how changes in AMPK could affect ATP turnover or any other component of energy flux. To the contrary, changes in muscle AMPK level or signalling are likely to be the consequence of, rather than cause of, changes in muscle metabolic rate. Hence, in terms of applicability to the energetics of muscle contraction or any other metabolic consequence of physical exercise, the hypothesis lacked a guard against tests such as those imposed by McConell and colleagues, who uncoupled changes in metabolic rate and energy substrate partitioning from changes in AMPK signalling in muscles of men studied before and after short-term exercise training. While the AMPK hypothesis lacked a necessary component of metabolic regulation, the hypothesis did contain a component to explain energy substrate partitioning during exercise. However, by predicting that AMPK signalling could simultaneously increase working muscle glucose disposal and lipid oxidation, proponents of the hypothesis failed to appreciate classic results of indirect calorimetry on body respiratory exchange ratio (RER) or more recent results on muscle respiratory quotient (RQ) or blood glucose and fatty acid flux rates during exercise (Brooks et al. 2004). Whether from perspectives of the Randle Cycle (Randle, 1995) or Crossover Concept (Brooks & Mercier, 1994), up-regulation of the use of one energy source (e.g. glucose) should down-regulate use of other sources (e.g. lipid). The proposition that AMPK could signal increments in both glucose and lipid metabolism in working muscle was untenable as it is contrary to experience and predictions of models of metabolic regulation. And, in terms of the AMPK hypothesis itself, alarms should have gone off when it was observed that malonyl-CoA levels did not change in working human muscle and remained at a level well above the IC50 (Brooks et al. 2004). Factors that regulate muscle glycolytic and oxidative energy fluxes are powerful, well known and independent of AMPK signalling (Kushmerick & Conley, 2002). Hence, it is not surprising that the purported, but subtle, effects of AMPK signalling are overridden during contraction. But, when exercise stops RER and RQ decline, and relative lipid oxidation increases whereas carbohydrate oxidation decreases (Brooks et al. 2004). Can it then be that the impact of AMPK signalling emerges after exercise? As untenable as the AMPK signalling hypothesis is for muscle exercise, it would be a pity to now suddenly abandon it based on the study of McConnell et al. In retrospect, their efforts were necessary, but results were predictable based on results of many previous investigations. In hindsight, because consequences of AMPK signalling are easily overridden during muscle contraction when energy flux rate can increase one or two orders of magnitude, invocation of the pathway as a means to regulate metabolic rate and energy substrate partitioning during physical activity may have been misguided. It is likely that the real importance of AMPK signalling, or its absence, may emerge in other, near basal conditions such as recovery from physical activity, space flight, postprandial rest in healthy individuals or those suffering from obesity, type 2 diabetes, or other metabolic diseases where small, but persistent effects on energy substrate partitioning may have major long-term consequences. And finally, the paper of McConnell and colleagues reminds us that homeostatic regulation of high flux systems typically requires redundant controls. Such systems are seldom regulated by a single factor. Perhaps the influence of AMPK signalling on muscle metabolism during exercise is analogous to the role of hydrogen ion in the regulation of pulmonary minute ventilation and muscle blood flow. By its nature, general understanding in well-developed sciences such as physiology possesses a degree of inertia. Ultimately, science advances because outstanding hypotheses are articulated (e.g. Winder, 2001) and aggressively tested. McConnell and colleagues have tested aspects of the ‘metabolic governor’ hypothesis. Now, the actual role and conditions under which changes in AMPK affect the regulation of muscle metabolism need to be determined.

Intestinal inflammatory diseases significantly affect animal health, primarily by disrupting intestinal barrier function. Indole-3-carboxaldehyde (IAld), a key metabolite of tryptophan derived from gut microbiota, exhibits protective properties against intestinal inflammatory diseases. The regulatory mechanism by which IAld modulates intestinal barrier function requires further investigation. An intestinal epithelial cell injury model was established by tumor necrosis factor-alpha (TNF-α) stimulation, alongside a mouse colitis model induced by dextran sulfate sodium (DSS) administration. Intestinal barrier function was assessed by immunoblotting, immunofluorescence, in vitro permeability assays, and histopathological analysis. Mitochondrial integrity and function were evaluated using JC-1 staining and transmission electron microscopy. Additionally, key components of the aryl hydrocarbon receptor (AhR)/AMP-activated protein kinase (AMPK) signaling pathway were analyzed using immunoblotting, immunofluorescence, and immunoprecipitation techniques. Our findings demonstrate that IAld treatment significantly enhanced tight junction protein expression in intestinal epithelial cells and effectively attenuated TNF-α-induced intestinal barrier injury. IAld activated cellular AMPK signaling, promoting autophagy, maintaining mitochondrial homeostasis, and ultimately improving intestinal barrier function. Importantly, the activation of AMPK signaling by IAld was found to be dependent on the AhR, as evidenced by the AhR-specific inhibitor CH-223191, which abolished both IAld-induced AMPK activation and enhancement of intestinal barrier integrity. Furthermore, in vivo< experiments confirmed that IAld ameliorated intestinal barrier dysfunction and mitochondrial damage in DSS-induced colitis mice, whereas pharmacological inhibition of AMPK largely abrogated these protective effects. Our findings demonstrate that IAld effectively preserves intestinal barrier integrity, highlighting its potential application in the treatment of intestinal inflammatory diseases in both animals and humans.

Mitogen-activated protein kinase (MAPK) pathways are involved in the regulation of cellular responses, including cell proliferation, differentiation, cell growth, and apoptosis. Because these responses are tightly related to cellular energy level, AMP-activated protein kinase (AMPK), which plays an essential role in energy homeostasis, has emerged as another key regulator. In the present study, we demonstrate a novel signal network between AMPK and MAPK in HCT116 human colon carcinoma. Glucose deprivation activated AMPK and three MAPK subfamilies, extracellular signal-regulated kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), and p38 MAPK. Under these conditions, inhibition of endogenous AMPK by expressing a dominant-negative form significantly potentiated ERK activation, indicating that glucose deprivation-induced AMPK is specifically antagonizing ERK activity in HCT116 cells. Moreover, we provide novel evidence that AMPK activity is critical for p53-dependent expression of dual-specificity phosphatase (DUSP) 1 & 2, which are negative regulators of ERK. Notably, ERK exhibits pro-apoptotic effects in HCT116 cells under glucose deprivation. Collectively, our data suggest that AMPK protects HCT116 cancer cells from glucose deprivation, in part, via inducing DUSPs, which suppresses pro-apoptotic ERK, further implying that a signal network between AMPK and ERK is a critical regulatory point in coupling the energy status of the cell to the regulation of cell survival.

Pectin is a complex polysaccharide found in plant cell walls and interlayers. As a food component, pectin is benefit for regulating intestinal flora. Metabolites of intestinal flora, including short-chain fatty acids (SCFAs), bile acids (BAs) and lipopolysaccharides (LPS), are involved in blood glucose regulation. SCFAs promote insulin synthesis through the intestine-GPCRs-derived pathway and hepatic adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway to promote hepatic glycogen synthesis. On the one hand, BAs stimulate intestinal L cells and pancreatic α cells to secrete Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) through receptors G protein-coupled receptor (TGR5) and farnesoid X receptor (FXR). On the other hand, BAs promote hepatic glycogen synthesis through AMPK pathway. LPS inhibits the release of inflammatory cytokines through Toll-like receptors (TLRs)-myeloid differentiation factor 88 (MYD88) pathway and mitogen-activated protein kinase (MAPK) pathway, thereby alleviating insulin resistance (IR). In brief, both SCFAs and BAs promote GLP-1 secretion through different pathways, employing strategies of increasing glucose consumption and decreasing glucose production to maintain normal glucose levels. Notably, pectin can also directly inhibit the release of inflammatory cytokines through the -TLRs-MYD88 pathway. These data provide valuable information for further elucidating the relationship between pectin-intestinal flora-glucose metabolism.