Sirtuins are important regulators of glucose and fat metabolism, sirtuin activation has been proposed as a therapeutic target for insulin resistance diabetes. We have shown leucine to increase mitochondrial biogenesis oxidation via Sirt1 dependent pathways. Resveratrol is widely recognized activator Sirt; however, the biologically-effective high concentrations used in cell animal studies generally impractical or difficult achieve humans. Accordingly, we sought determine whether would exhibit...

The AMPK-Sirt1 pathway is an important regulator of energy metabolism and therefore a potential target for prevention therapy metabolic diseases. We recently demonstrated leucine its metabolite β-hydroxy-β-methylbutyrate (HMB) to synergize with low-dose resveratrol (200 nM) activate sirtuin signaling stimulate metabolism. Here we show that exerts direct effect on Sirt1 kinetics, reducing Km NAD+ by >50% enabling low doses further the enzyme (p = 0.012). To test which structure elements are...

Leucine stimulates tissue protein synthesis and may also attenuate adiposity by increasing fatty acid oxidation mitochondrial biogenesis in muscle adipocytes. Accordingly, the effects of a nutraceutical containing 2.25 g leucine 30 mg pyridoxine (Vitamin B6) (NuFit active blend) were tested cell culture clinical trial. 3T3L1 adipocytes treated with (0.25 mM or 0.5 mM) and/or Pyridoxal Phosphate (PLP) (50 nM 100 nM) for 48 h. For trial, twenty overweight obese subjects received NuFit blend...

Recent data from this laboratory suggest that components of dairy foods may serve as activators SIRT1 (Silent Information Regulator Transcript 1), and thereby participate in regulation glucose lipid metabolism. In study, an ex-vivo/in-vitro approach was used to examine the integrated effects diets on activation two key target tissues (adipose muscle tissue).Serum overweight obese subjects fed low or high for 28 days added culture medium (similar conditioned media) treat cultured adipocytes...

Purpose: Leucine activates SIRT1/AMP-activated protein kinase (AMPK) signaling and markedly potentiates the effects of other sirtuin AMPK activators on insulin lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide–cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α)-mediated effects. Methods: We evaluated potential synergy between leucine PDE5i sensitivity...

Sirt1, AMPK, and eNOS modulate hepatic energy metabolism inflammation are key players in the development of NASH. L-leucine, an allosteric Sirt1 activator, synergizes with low doses metformin or sildenafil on AMPK-eNOS-Sirt1 pathway to reverse mild NAFLD preclinical mouse models. Here we tested a possible multicomponent synergy yield greater therapeutic efficacy NAFLD/NASH. Liver cells macrophages atherogenic diet induced NASH model was treated two-way three-way combinations. The combination...

Abstract Colorectal cancer (CRC) cells shift metabolism toward aerobic glycolysis and away from using oxidative substrates such as butyrate. Pyruvate kinase M1/2 (PKM) is an enzyme that catalyzes the last step in glycolysis, which converts phosphoenolpyruvate to pyruvate. M1 M2 are alternatively spliced isoforms of Pkm gene. The PKM1 isoform promotes metabolism, whereas PKM2 enhances glycolysis. We hypothesize PKM involved butyrate oxidation towards CRC cells. Here, we find increased...

Oxidative and inflammatory stress have been implicated as major contributors to the aging process. Dietary Ca reduced both factors in short-term interventions, while milk exerted a greater effect than supplemental Ca. In this work, we examined effects of life-long dairy calcium on lifespan life-span related biomarkers aP2-agouti transgenic (model diet-induced obesity) wild-type mice fed obesigenic diets until their death. These data demonstrate that exerts sustained resulting attenuated...

High-calcium diets modulate energy metabolism and suppress inflammatory stress. These effects are primarily mediated by calcium suppression of calcitriol. We have now investigated the effect additional components in dairy products [branched-chain amino acids (BCAA) angiotensin-converting enzyme inhibitors (ACEi)] on adipocyte muscle an animal model diet-induced obesity.aP2-agouti mice were fed four different 70% restricted for 6 weeks: basal-restricted diet (0.4% Ca), nonfat dry milk (1.2%...

Sirt1 (Sirtuin 1), AMPK (AMP-activated protein kinase), and eNOS (endothelial nitric oxide synthase) modulate hepatic energy metabolism inflammation play a major role in the development of NASH. Cyclic nucleotide phosphodiesterases (PDEs) an important signal transduction by modulating intracellular levels cyclic nucleotides. We previously found PDE5 inhibitor sildenafil to synergize with leucine leucine-metformin combinations preclinical studies NASH obesity. However, efficacy is diminished...

FNDC5 is a muscle membrane protein stimulated by PGC1‐α; when cleaved, it releases irisin, which stimulates UCP1 expression and browning of white adipose tissue. We recently found leucine (0.5 mM) its metabolite, HMB (5 μM), to synergize with low‐dose polyphenols activate sirtuin signaling, resulting in significant increases fatty acid oxidation (FAO) adipocytes myotubes. Here we report that treating conditioned media from myotubes treated these combinations also results increased FAO...

We recently demonstrated synergy between low dose resveratrol (200 nM) with leucine or its metabolite HMB on energy metabolism. have now assessed potential of other polyphenols and HMB. Dose‐response curves for fatty acid oxidation (FAO) were constructed the highest non‐effective (typically 1 – 10 was combined either (0.5 mM) (5 μM) to treat adipocytes myotubes 24h. Significant detected stilbenes (resveratrol, piceatannol) a stilbene‐containing grape seed extract, resulting in stimulation...

Previous data from this lab demonstrates that leucine stimulates Sirt1 expression and activity, as well downstream mitochondrial biogenesis fatty acid oxidation in myotubes. We have now investigated the effects of its metabolites on both Sirt1, Sirt3 AMP‐activated protein kinase (AMPK) 3T3‐L1adipocytes. Leucine (0.5 mM) stimulated ~2‐fold (p=0.009) but not while it's (α‐keto isocaproic [KIC] β‐hydroxy‐β‐methyl butyrate [HMB]) exerted little effect; neither valine nor alanine (controls) any...

Previous data demonstrate the BCAA leucine (Leu) to stimulate AMPK and Sirt1 signaling in vitro vivo. Nicotinic acid (NA) has been used as a highly effective treatment of dislipidemias; however, its poorly tolerated side effects (severe vasodilation flushing at high doses) limits use drug. Since it increases NAD+ thereby activates Sirt1, we tested synergistic (0.5 mM) low dose NA (10 nM) on AMPK/Sirt1 downstream cell culture C. elegans. The NA‐Leucine combination increased P‐AMPK by 80%,...

Obesity alters the balance of adipose tissue‐derived cytokines and increases airway inflammation hyper‐reactivity. We previously found calcitriol leucine to exert opposing effects on tissue cytokine production, systemic inflammation, monocyte adherence vascular endothelial cells. now propose that dietary calcium (via suppression calcitriol) attenuate reactivity by suppressing TNF‐α enhancing adiponectin release. Human adipocytes were treated with (10 nM) (0.5 mM) for 48 h conditioned medium...

We recently demonstrated leucine and HMB synergy with resveratrol other polyphenols to activate sirtuin signaling downstream pathways, including mitochondrial biogenesis fatty acid oxidation (FAO). Since also activates Sirt1 via PDE inhibition AMPK activation, we determined between or low‐dose inhibitors in stimulating aerobic metabolism adipocytes myotubes. were studied at concentrations that exerted no independent effects the systems (0.1 – 10 nM); only 5 (sildenafil icariin) exhibited...

Leucine activates Sirt1 signaling and markedly potentiates the effects of other activators on sirtuin downstream effects, including insulin signaling. PDE5 inhibition increases NO‐cGMP signaling, converging with sirtuins PGC‐1 mitochondrial biogenesis thereby modulating sensitivity. We confirmed this synergy in vitro, demonstrating between leucine (0.5 mM) two inhibitors, sildenafil natural flavonol icariin (0.1‐10 nM) aerobic metabolism, sensitivity myotubes adipocytes. Effects glycemic...

We recently demonstrated leucine to modulate energy partitioning between adipose tissue and muscle. Further, exhibits a synergy with B6, resulting in reduced adipocyte lipid storage coupled increased muscle fat oxidation. A nutraceutical (NuShape) containing 2.25 g 30 mg B6 oxidation by >;30 g/d 28‐day RCT. To evaluate the efficacy of this combination modulating body weight composition, we conducted two 24‐week placebo‐controlled RCTs, one maintenance (n=20) hypocaloric (−500 kcal/d;...