Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 ...healthy, obese men with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.
► Resveratrol reduced sleeping metabolic rate in human, mimicking calorie restriction ► Resveratrol improved mitochondrial metabolism through the AMPK-SIRT1-PGC-1α axis ► Resveratrol decreased hepatic and increased muscle lipid content ► Resveratrol reduced inflammation markers in plasma and muscle
Abstract
Branched-chain amino acid (BCAA) catabolism has been considered to have an emerging role in the pathogenesis of metabolic disturbances in obesity and type 2 diabetes (T2D). Several studies ...showed elevated plasma BCAA levels in humans with insulin resistance and patients with T2D, although the underlying reason is unknown. Dysfunctional BCAA catabolism could theoretically be an underlying factor. In vitro and animal work collectively show that modulation of the BCAA catabolic pathway alters key metabolic processes affecting glucose homeostasis, although an integrated understanding of tissue-specific BCAA catabolism remains largely unknown, especially in humans. Proof-of-concept studies in rodents -and to a lesser extent in humans – strongly suggest that enhancing BCAA catabolism improves glucose homeostasis in metabolic disorders, such as obesity and T2D. In this review, we discuss several hypothesized mechanistic links between BCAA catabolism and insulin resistance and overview current available tools to modulate BCAA catabolism in vivo. Furthermore, this review considers whether enhancing BCAA catabolism forms a potential future treatment strategy to promote metabolic health in insulin resistance and T2D.
Lipotoxicity in type 2 diabetic cardiomyopathy van de Weijer, Tineke; Schrauwen-Hinderling, Vera B; Schrauwen, Patrick
Cardiovascular research,
10/2011, Volume:
92, Issue:
1
Journal Article
Peer reviewed
Open access
As obesity and type 2 diabetes are becoming an epidemic in westernized countries, the incidence and prevalence of obesity- and diabetes-related co-morbidities are increasing. In type 2 diabetes ...ectopic lipid accumulation in the heart has been associated with cardiac dysfunction and apoptosis, a process termed lipotoxicity. Since cardiovascular diseases are the main cause of death in diabetic patients, diagnosis and treatment become increasingly important. Although ischaemic heart disease is a major problem in diabetes, non-ischaemic heart disease (better known as diabetic cardiomyopathy) becomes increasingly important with respect to the impairment of cardiac function and mortality in type 2 diabetes. The underlying aetiology of diabetic cardiomyopathy is incompletely understood but is beginning to be elucidated. Various mechanisms have been proposed that may lead to lipotoxicity. Therefore, this review will focus on the mechanisms of cardiac lipid accumulation and its relation to the development of cardiomyopathy.
Circadian rhythms in mitochondrial respiration de Goede, Paul; Wefers, Jakob; Brombacher, Eline Constance ...
Journal of molecular endocrinology,
04/2018, Volume:
60, Issue:
3
Journal Article
Peer reviewed
Open access
Many physiological processes are regulated with a 24-h periodicity to anticipate the environmental changes of daytime to nighttime and vice versa. These 24-h regulations, commonly termed circadian ...rhythms, among others control the sleep-wake cycle, locomotor activity and preparation for food availability during the active phase (daytime for humans and nighttime for nocturnal animals). Disturbing circadian rhythms at the organ or whole-body level by social jetlag or shift work, increases the risk to develop chronic metabolic diseases such as type 2 diabetes mellitus. The molecular basis of this risk is a topic of increasing interest. Mitochondria are essential organelles that produce the majority of energy in eukaryotes by converting lipids and carbohydrates into ATP through oxidative phosphorylation. To adapt to the ever-changing environment, mitochondria are highly dynamic in form and function and a loss of this flexibility is linked to metabolic diseases. Interestingly, recent studies have indicated that changes in mitochondrial morphology (i.e., fusion and fission) as well as generation of new mitochondria are dependent on a viable circadian clock. In addition, fission and fusion processes display diurnal changes that are aligned to the light/darkness cycle. Besides morphological changes, mitochondrial respiration also displays diurnal changes. Disturbing the molecular clock in animal models leads to abrogated mitochondrial rhythmicity and altered respiration. Moreover, mitochondrial-dependent production of reactive oxygen species, which plays a role in cellular signaling, has also been linked to the circadian clock. In this review, we will summarize recent advances in the study of circadian rhythms of mitochondria and how this is linked to the molecular circadian clock.
Reduced mitochondrial capacity in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus (T2DM). However, data obtained from human subjects ...concerning this putative relation indicate that the mitochondrial defect observed in diabetic muscle might be secondary to the insulin-resistant state instead of being a causal factor. Nonetheless, diminished mitochondrial function, even secondary to insulin resistance, may accelerate lipid deposition in non-adipose tissues and aggravate insulin resistance. Indeed, improving mitochondrial capacity via exercise training and calorie restriction is associated with positive metabolic health effects. Here we review muscle mitochondrial dysfunction in humans and propose that targeting muscle mitochondria to improve muscle oxidative capacity should be considered as a strategy for improving metabolic health.
Brown fat generates heat via the mitochondrial uncoupling protein UCP1, defending against hypothermia and obesity. Recent data suggest that there are two distinct types of brown fat: classical brown ...fat derived from a myf-5 cellular lineage and UCP1-positive cells that emerge in white fat from a non-myf-5 lineage. Here, we report the isolation of “beige” cells from murine white fat depots. Beige cells resemble white fat cells in having extremely low basal expression of UCP1, but, like classical brown fat, they respond to cyclic AMP stimulation with high UCP1 expression and respiration rates. Beige cells have a gene expression pattern distinct from either white or brown fat and are preferentially sensitive to the polypeptide hormone irisin. Finally, we provide evidence that previously identified brown fat deposits in adult humans are composed of beige adipocytes. These data provide a foundation for studying this mammalian cell type with therapeutic potential.
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► A subset of precursor cells from white fat gives rise to beige adipocytes ► Beige adipocytes have a highly inducible thermogenic capacity upon stimulation ► Beige adipocytes express distinct genes and are sensitive to irisin ► “Brown” fat in human adults is composed primarily of beige adipocytes
A subset of adipocytes in adult human fat depots shows a distinctive gene expression pattern and deploys a thermogenic program in response to the hormone irisin. These so-called beige cells may therefore represent a therapeutic target for treating obesity and associated metabolic disorders.
Hepatic steatosis is associated with poor cardiometabolic health, with de novo lipogenesis (DNL) contributing to hepatic steatosis and subsequent insulin resistance. Hepatic saturated fatty acids ...(SFA) may be a marker of DNL and are suggested to be most detrimental in contributing to insulin resistance. Here, we show in a cross-sectional study design (ClinicalTrials.gov ID: NCT03211299) that we are able to distinguish the fractions of hepatic SFA, mono- and polyunsaturated fatty acids in healthy and metabolically compromised volunteers using proton magnetic resonance spectroscopy (
H-MRS). DNL is positively associated with SFA fraction and is elevated in patients with non-alcoholic fatty liver and type 2 diabetes. Intriguingly, SFA fraction shows a strong, negative correlation with hepatic insulin sensitivity. Our results show that the hepatic lipid composition, as determined by our
H-MRS methodology, is a measure of DNL and suggest that specifically the SFA fraction may hamper hepatic insulin sensitivity.
Elevations in plasma branched-chain amino acid (BCAA) levels associate with insulin resistance and type 2 diabetes (T2D). Pre-clinical models suggest that lowering BCAA levels improve glucose ...tolerance, but data in humans are lacking. Here, we used sodium phenylbutyrate (NaPB), an accelerator of BCAA catabolism, as tool to lower plasma BCAA levels in patients with T2D, and evaluate its effect on metabolic health. This trial (NetherlandsTrialRegister: NTR7426) had a randomized, placebo-controlled, double-blind cross-over design and was performed in the Maastricht University Medical Center (MUMC+), the Netherlands, between February 2019 and February 2020. Patients were eligible for the trial if they were 40-75years, BMI of 25-38 kg/m², relatively well-controlled T2D (HbA1C < 8.5%) and treated with oral glucose-lowering medication. Eighteen participants were randomly assigned to receive either NaPB 4.8 g/m²/day and placebo for 2 weeks via controlled randomization and sixteen participants completed the study. The primary outcome was peripheral insulin sensitivity. Secondary outcomes were ex vivo muscle mitochondrial oxidative capacity, substrate oxidation and ectopic fat accumulation. Fasting blood samples were collected to determine levels of BCAA, their catabolic intermediates, insulin, triglycerides, free fatty acids (FFA) and glucose. NaPB led to a robust 27% improvement in peripheral insulin sensitivity compared to placebo (ΔRd:13.2 ± 1.8 vs. 9.6 ± 1.8 µmol/kg/min, p = 0.02). This was paralleled by an improvement in pyruvate-driven muscle mitochondrial oxidative capacity and whole-body insulin-stimulated carbohydrate oxidation, and a reduction in plasma BCAA and glucose levels. No effects were observed on levels of insulin, triglycerides and FFA, neither did fat accumulation in muscle and liver change. No adverse events were reported. These data establish the proof-of-concept in humans that modulating the BCAA oxidative pathway may represent a potential treatment strategy for patients with T2D.
Mitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid IMCL) have been linked to development of type 2 diabetes. We examined whether exercise training ...could restore mitochondrial function and insulin sensitivity in patients with type 2 diabetes.
Eighteen male type 2 diabetic and 20 healthy male control subjects of comparable body weight, BMI, age, and VO2max participated in a 12-week combined progressive training program (three times per week and 45 min per session). In vivo mitochondrial function (assessed via magnetic resonance spectroscopy), insulin sensitivity (clamp), metabolic flexibility (indirect calorimetry), and IMCL content (histochemically) were measured before and after training.
Mitochondrial function was lower in type 2 diabetic compared with control subjects (P = 0.03), improved by training in control subjects (28% increase; P = 0.02), and restored to control values in type 2 diabetic subjects (48% increase; P < 0.01). Insulin sensitivity tended to improve in control subjects (delta Rd 8% increase; P = 0.08) and improved significantly in type 2 diabetic subjects (delta Rd 63% increase; P < 0.01). Suppression of insulin-stimulated endogenous glucose production improved in both groups (-64%; P < 0.01 in control subjects and -52% in diabetic subjects; P < 0.01). After training, metabolic flexibility in type 2 diabetic subjects was restored (delta respiratory exchange ratio 63% increase; P = 0.01) but was unchanged in control subjects (delta respiratory exchange ratio 7% increase; P = 0.22). Starting with comparable pretraining IMCL levels, training tended to increase IMCL content in type 2 diabetic subjects (27% increase; P = 0.10), especially in type 2 muscle fibers.
Exercise training restored in vivo mitochondrial function in type 2 diabetic subjects. Insulin-mediated glucose disposal and metabolic flexibility improved in type 2 diabetic subjects in the face of near-significantly increased IMCL content. This indicates that increased capacity to store IMCL and restoration of improved mitochondrial function contribute to improved muscle insulin sensitivity.
Nicotinamide riboside (NR) is an NAD+ precursor that boosts cellular NAD+ concentrations. Preclinical studies have shown profound metabolic health effects after NR supplementation.
We aimed to ...investigate the effects of 6 wk NR supplementation on insulin sensitivity, mitochondrial function, and other metabolic health parameters in overweight and obese volunteers.
A randomized, double-blinded, placebo-controlled, crossover intervention study was conducted in 13 healthy overweight or obese men and women. Participants received 6 wk NR (1000 mg/d) and placebo supplementation, followed by broad metabolic phenotyping, including hyperinsulinemic-euglycemic clamps, magnetic resonance spectroscopy, muscle biopsies, and assessment of ex vivo mitochondrial function and in vivo energy metabolism.
Markers of increased NAD+ synthesis—nicotinic acid adenine dinucleotide and methyl nicotinamide—were elevated in skeletal muscle after NR compared with placebo. NR increased body fat-free mass (62.65% ± 2.49% compared with 61.32% ± 2.58% in NR and placebo, respectively; change: 1.34% ± 0.50%, P = 0.02) and increased sleeping metabolic rate. Interestingly, acetylcarnitine concentrations in skeletal muscle were increased upon NR (4558 ± 749 compared with 3025 ± 316 pmol/mg dry weight in NR and placebo, respectively; change: 1533 ± 683 pmol/mg dry weight, P = 0.04) and the capacity to form acetylcarnitine upon exercise was higher in NR than in placebo (2.99 ± 0.30 compared with 2.40 ± 0.33 mmol/kg wet weight; change: 0.53 ± 0.21 mmol/kg wet weight, P = 0.01). However, no effects of NR were found on insulin sensitivity, mitochondrial function, hepatic and intramyocellular lipid accumulation, cardiac energy status, cardiac ejection fraction, ambulatory blood pressure, plasma markers of inflammation, or energy metabolism.
NR supplementation of 1000 mg/d for 6 wk in healthy overweight or obese men and women increased skeletal muscle NAD+ metabolites, affected skeletal muscle acetylcarnitine metabolism, and induced minor changes in body composition and sleeping metabolic rate. However, no other metabolic health effects were observed. This trial was registered at clinicaltrials.gov as NCT02835664
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