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Aims/hypothesisWhether metformin reduces cardiovascular or cancer risk is unclear owing to concerns over immortal time bias and confounding in observational studies. This study evaluated the effect of AMP-activated protein kinase (AMPK), the target of metformin, on risk of cardiovascular disease and cancer.MethodsThis is a Mendelian randomisation design, using AMPK, the pharmacological target of metformin, to infer the AMPK pathway-dependent effects of metformin on risk of cardiovascular disease and cancer in participants of white British ancestry in the UK Biobank.ResultsA total of 391,199 participants were included (mean age 56.9 years; 54.1% women), including 26,690 cases of type 2 diabetes, 38,098 cases of coronary artery disease and 80,941 cases of overall cancer. Genetically predicted reduction in HbA1c (%) instrumented by AMPK variants was associated with a 61% reduction in risk of type 2 diabetes (OR 0.39; 95% CI 0.20, 0.78; p = 7.69 × 10−3), a 53% decrease in the risk of coronary artery disease (OR 0.47; 95% CI 0.26, 0.84; p = 0.01) and a 44% decrease in the risk of overall cancer (OR 0.56; 95% CI 0.36, 0.85; p = 7.23 × 10−3). Results were similar using median or quartiles of AMPK score, with dose–response effects (p for trend = 4.18 × 10−3 for type 2 diabetes, 4.37 × 10−3 for coronary artery disease and 4.04 × 10−3 for overall cancer).Conclusions/interpretationThis study provides some genetic evidence that AMPK activation by metformin may protect against cardiovascular disease and cancer, which needs to be confirmed by randomised controlled trials.

Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NADPH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer mouse models, we show that G6PD ablation significantly suppresses Kras G12D/+ ;Lkb1 -/- (KL) but not Kras G12D/+ ;P53 -/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics reveal that G6PD ablation significantly impairs NADPH generation, redox balance, and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation activates p53, suppressing tumor growth. As tumors progress, G6PD-deficient KL tumors increase an alternative NADPH source from serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations. Cancer cells rely on NADPH to manage oxidative stress and support biosynthesis. Here, the authors show that glucose-6-phosphate dehydrogenase (G6PD) ablation suppresses KRAS -driven lung tumours with LKB1 deficiency, but not with P53 deficiency, by impairing NADPH production, suggesting a potential therapeutic strategy.

Physical activity or metformin enhances insulin sensitivity and opposes the progression from prediabetes to type 2 diabetes. The combination may be more effective because each treatment stimulates AMP-activated protein kinase activity in skeletal muscle. We evaluated the effects of exercise training plus metformin on insulin sensitivity in men and women with prediabetes, compared with each treatment alone. For 12 weeks, men and women with prediabetes were assigned to the following groups: placebo (P), 2,000 mg/day metformin (M), exercise training with placebo (EP), or exercise training with metformin (EM) (n = 8 per group). Before and after the intervention, insulin sensitivity was measured by euglycemic hyperinsulinemic (80 mU/m(2)/min) clamp enriched with [6,6-(2)H]glucose. Changes due to intervention were compared across groups by repeated-measures ANOVA. All three interventions increased insulin sensitivity (P < 0.05) relative to the control group. The mean rise was 25-30% higher after EP than after either EM or M, but this difference was not significant. Insulin sensitivity was considerably higher after 12 weeks of exercise training and/or metformin in men and women with prediabetes. Subtle differences among condition means suggest that adding metformin blunted the full effect of exercise training.

Background/Objectives: Obesity accelerates metabolic aging through oxidative stress, inflammation, and mitochondrial dysfunction. AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are nutrient-sensing pathways regulating metabolism. AMPK promotes energy metabolism and autophagy, while excessive mTOR activity contributes to aging. Intermittent fasting (IF), including time-restricted feeding (TRF)—limiting food intake to a 6 h window (18:6)—and alternate-day modified fasting (ADMF)—alternating 24 h fasting (≤25% daily caloric intake) with unrestricted feeding—may improve metabolic regulation. However, their effects on AMPK, mTOR, and metabolic age remain unclear. Methods: This quasi-experimental pre-test–post-test control group study compared the TRF and ADMF on metabolic age, AMPK, and mTOR in young obese women. Twenty-four participants (mean age: 21.29 ± 1.76 years; body fat: 36.92 ± 3.18%; BMI: 29.68 ± 3.70 kg/m2) were initially matched by BMI and assigned to Control, TRF, and ADMF groups. A total of 4 participants (1 Control, 3 ADMF) were excluded due to outlier values, yielding final group sizes: Control (n = 7), TRF (n = 8), and ADMF (n = 5). The intervention lasted 20 days. Results: A significant decrease in AMPK levels was observed in the ADMF group (p = 0.043), while changes in the TRF and Control groups were not significant. mTOR levels showed a decreasing trend but were not statistically significant. No significant changes were found in metabolic age. Conclusions: Twenty days of intermittent fasting intervention did not significantly affect AMPK, mTOR, or metabolic age in young obese women. TRF may more effectively enhance AMPK and reduce mTOR, while ADMF may better reduce metabolic age.

One of the key events in cancer development is the ability of tumor cells to overcome nutrient deprivation and hypoxia. Among proteins performing metabolic adaptation to the various cellular nutrient conditions, liver kinase B 1 (LKB1) and its main downstream target adenosine monophosphate (AMP)-activated protein kinase α (AMPKα) are important sensors of energy requirements within the cell. Although LKB1 was originally described as a tumor suppressor, given its role in metabolism, it potentially acts as a double-edged sword. AMPKα, a master regulator of cell energy demands, is activated when ATP level drops under a certain threshold, responding accordingly through its downstream targets. Twelve downstream kinase targets of LKB1 have been described as AMPKα-like proteins. This group is comprised of novel (nua) kinase family (NUAK) kinases (NUAK1 and 2) linked to cell cycle progression and ultraviolet (UV)-damage; microtubule affinity regulating kinases (MARKs) (MARK1, MARK2, MARK3, and MARK4) that are involved in cell polarity; salt inducible kinases (SIK) (SIK1, SIK2, also known as Qin-induced kinase or QIK and SIK3) that are implicated in cell metabolism and adipose tissue development and mitotic regulation; maternal embryonic leuzine zipper kinase (MELK) that regulate oocyte maturation; and finally brain selective kinases (BRSKs) (BRSK1 and 2), which have been mainly characterized in the brain due to their role in neuronal polarization. Thus, many efforts have been made in order to harness LKB1 kinase and its downstream targets as a possible therapeutic hub in tumor development and propagation. In this review, we describe LKB1 and its downstream target AMPK summarize major functions of various AMPK-like proteins, while focusing on biological functions of BRSK1 and 2 in different models.

A12-week experiment was conducted to evaluate the influences of thiamine ongrowth performance, and intestinal mitochondrial biogenesis and function of Megalobramaamblycephala fed a high-carbohydrate (HC) diet. Fish (24·73 (sem 0·45) g) were randomly assigned to one of four diets: two carbohydrate (CHO) levels (30 and 45 %) and two thiamine levels (0 and 1·5 mg/kg). HC diets significantly decreased DGC, GRMBW, FIMBW, intestinal activities of amylase, lipase, Na+, K+-ATPase, CK, complexes I, III and IV, intestinal ML, number of mitochondrial per field, ΔΨm, the P-AMPK: T-AMPK ratio, PGC-1β protein expression as well as the transcriptions of AMPKα1, AMPKα2, PGC-1β, mitochondrial transcription factor A, Opa-1, ND-1 and COX-1 and 2, while the opposite was true for ATP, AMP and reactive oxygen species, and the transcriptions of dynamin-related protein-1, fission-1 and mitochondrial fission factor. Dietarythiamine concentrations significantly increased DGC, GRMBW, intestinal activities of amylase, Na+, K+-ATPase, CK, complexes I and IV, intestinal ML, number of mitochondrial per field, ΔΨm, the P-AMPK:T-AMPK ratio, PGC-1β protein expression as well as the transcriptions of AMPKα1, AMPKα2, PGC-1β, Opa-1, ND-1, COX-1 and 2, SGLT-1 and GLUT-2. Furthermore, a significant interaction between dietary CHO and thiamine was observed in DGC, GRMBW, intestinal activities of amylase, CK, complexes I and IV, ΔΨm, the AMP:ATP ratio, the P-AMPK:T-AMPK ratio, PGC-1β protein expression as well as the transcriptions of AMPKα1, AMPKα2, PGC-1β, Opa-1, COX-1 and 2, SGLT-1 and GLUT-2. Overall, thiamine supplementation improved growth performance, and intestinal mitochondrial biogenesis and function of M. amblycephala fed HC diets.

Human gingival fibroblasts (HGnFs) maintain periodontal tissue homeostasis through active proliferation and migration. Clinically, it is considered that the wound-healing ability of the gingival tissue is maintained even in environments with insufficient supply of nutrients, such as glucose, immediately after periodontal surgery. However, the effects of such glucose-deficient environments on HGnFs remain unclear. This study aimed to investigate the effects of low-glucose environment on HGnFs homeostasis. We evaluated gingival wound healing by examining cell proliferation and migration and collagen synthesis in HGnFs cultured in 100, 50, 25, and 0 mg/dL glucose in vitro. The cellular stress levels were determined by measuring the lactate dehydrogenase (LDH) and reactive oxygen species (ROS) levels. The glucose metabolism of HGnFs in the low-glucose concentrations was studied by measuring glucose transporter type 1 (GLUT1) mRNA expression, glucose uptake assays, lactate and ATP productions. Molecular effects were examined with a focus on the LKB1-AMPK signaling pathway. Autophagy activity in glucose-deprived HGnFs was evaluated by measuring the levels of autophagy-related proteins. Low glucose levels increased cellular stress levels, autophagy activity, and enhanced glucose metabolism through the LKB1-AMPK signaling pathway, providing more ATPs to promote wound healing. Our results regarding glucose transfer suggest the rapid healing of gingival wounds.

Recent studies suggest that carbohydrate restriction can improve the training-induced adaptation of muscle oxidative capacity. However, the importance of low muscle glycogen on the molecular signaling of mitochondrial biogenesis remains unclear. Here, we compare the effects of exercise with low (LG) and normal (NG) glycogen on different molecular factors involved in the regulation of mitochondrial biogenesis. Ten highly trained cyclists ( V O 2max 65 ± 1 ml/kg/min, W max 387 ± 8 W) exercised for 60 min at approximately 64 % V O 2max with either low [166 ± 21 mmol/kg dry weight (dw)] or normal (478 ± 33 mmol/kg dw) muscle glycogen levels achieved by prior exercise/diet intervention. Muscle biopsies were taken before, and 3 h after, exercise. The mRNA of peroxisome proliferator-activated receptor-γ coactivator-1 was enhanced to a greater extent when exercise was performed with low compared with normal glycogen levels (8.1-fold vs. 2.5-fold increase). Cytochrome c oxidase subunit I and pyruvate dehydrogenase kinase isozyme 4 mRNA were increased after LG (1.3- and 114-fold increase, respectively), but not after NG. Phosphorylation of AMP-activated protein kinase, p38 mitogen-activated protein kinases and acetyl-CoA carboxylase was not changed 3 h post-exercise. Mitochondrial reactive oxygen species production and glutathione oxidative status tended to be reduced 3 h post-exercise. We conclude that exercise with low glycogen levels amplifies the expression of the major genetic marker for mitochondrial biogenesis in highly trained cyclists. The results suggest that low glycogen exercise may be beneficial for improving muscle oxidative capacity.

In the bone marrow, classical and plasmacytoid dendritic cells (DC) develop from the macrophage-DC precursor (MDP) through a common DC precursor (CDP) step. This developmental process receives essential input from the niche in which it takes place, containing endothelial cells (EC) among other cell types. Here we show that targeted deletion of serine/threonine kinase 11 ( Stk11 ) encoding tumor suppressor liver kinase b1 (Lkb1) in mouse ECs but not DCs, results in disrupted differentiation of MDPs to CDPs, severe reduction in mature DC numbers and spontaneous tumorigenesis. In wild type ECs, Lkb1 phosphorylates polypyrimidine tract binding protein 1 (Ptbp1) at threonine 138, which regulates stem cell factor ( Scf ) pre-mRNA splicing. In the absence of Lkb1, exon 6 of Scf is spliced out, leading to the loss of Scf secretion. Adeno-associated-virus-mediated delivery of genes encoding either soluble Scf or the phosphomimetic mutant Ptbp1 T138E proteins rescued the defects of MDP to CDP differentiation and DC shortage in the endothelium specific Stk11 knockout mice. In summary, endothelial Stk11 expression regulates DC differentiation via modulation of Scf splicing, marking the Stk11 -soluble-Scf axis as a potential cause of DC deficiency syndromes. In the bone marrow, dendritic cell development is governed by supporting cells, such as endothelial cells. Here authors show that expression of serine/threonine kinase 11 in endothelial cells regulates differentiation of dendritic cell precursors via modulating secretion of stem cell factor.

Acne vulgaris is a highly prevalent skin disorder characterized by hyperseborrhea, inflammation, and Propionibacterium acnes overgrowth. Only isotretinoin and hormonal therapy reduce sebum production. To identify a new drug candidate that modulates sebum, we examined the effects of EGCG, the major polyphenol in green tea, on human SEB-1 sebocytes and in patients with acne. In SEB-1 sebocytes, we found that EGCG reduced sebum by modulating the AMPK–SREBP-1 signaling pathway. EGCG also reduces inflammation by suppressing the NF-κB and AP-1 pathways. EGCG also induces cytotoxicity of SEB-1 sebocytes via apoptosis and decreases the viability of P. acnes, thus targeting almost all the pathogenic features of acne. Finally, and most importantly, EGCG significantly improved acne in an 8-week randomized, split-face, clinical trial, and was well tolerated. Our data provide a therapeutic rationale for the use of EGCG in acne.