Key points
Considerable controversy exists regarding the role of irisin, a putative exercise‐induced myokine, in human metabolism.
We therefore studied irisin and its precursor Fndc5 in obesity, ...type 2 diabetes and exercise.
Complex clinical studies combined with cell culture work revealed that Fndc5/irisin was decreased in type 2 diabetes in vivo, but not in muscle cells in vitro, indicating that diabetes‐related factor(s) regulate Fndc5/irisin in vivo.
Several attributes of type 2 diabetes, such as hyperglycaemia, triglyceridaemia, visceral adiposity and extramyocellular lipid deposition were negatively associated with adipose tissue Fndc5 mRNA and circulating irisin. Moreover, mimicking diabetic status in vitro by treating muscle cells with palmitate and glucose lowered Fndc5 mRNA.
Neither exercise training nor an acute exercise bout modulated circulating irisin or muscle Fndc5 expression. However, the associations between intensity of habitual physical activity, muscle volume, strength, contractility and circulating irisin provide a link between irisin and positive outcomes of increased physical activity.
Irisin was identified as a myokine secreted by contracting skeletal muscle, possibly mediating some exercise health benefits via ‘browning’ of white adipose tissue. However, a controversy exists concerning irisin origin, regulation and function in humans. Thus, we have explored Fndc5 gene and irisin protein in two clinical studies: (i) a cross‐sectional study (effects of type 2 diabetes (T2D) in drug‐naive men) and (ii) an intervention study (exercise effects in sedentary, overweight/obese individuals). Glucose tolerance and insulin sensitivity were assessed. Maximal aerobic capacity and muscle strength were measured before and after training. Body composition (magnetic resonance imaging), muscle and liver fat content (1H‐magnetic resonance spectroscopy (MRS)) and in vivo muscle metabolism (32P‐MRS) were determined. Skeletal muscle and subcutaneous abdominal adipose tissue samples were taken in the fasted state and during euglycaemic hyperinsulinaemia (adipose tissue) and before/after exercise training (muscle). We found that muscle Fndc5 mRNA was increased in prediabetes but not T2D. Fndc5 in adipose tissue and irisin in plasma were reduced in T2D by 40% and 50%, respectively. In contrast, T2D‐derived myotubes expressed/secreted the highest levels of Fndc5/irisin. Neither hyperinsulinaemia (adipose tissue/plasma) nor exercise (muscle/plasma) affected Fndc5/irisin in vivo. Circulating irisin was positively associated with muscle mass, strength and metabolism and negatively with fasting glycaemia. Glucose and palmitate decreased Fndc5 mRNA in myotubes in vitro. We conclude that distinct patterns of Fndc5/irisin in muscle, adipose tissue and circulation, and concordant in vivo down‐regulation in T2D, indicate that irisin might distinguish metabolic health and disease. Moreover, Fndc5/irisin was discordantly regulated in diabetic muscle and myotubes in vitro, suggesting that whole body factors, such as glucose and fatty acids, might be important for irisin regulation. Exercise did not affect Fndc5/irisin. However, irisin was positively linked to muscle mass, strength and metabolism, pointing to common regulatory factors and/or the potential for irisin to modify muscle phenotype.
Although exercise is an effective way to decrease the risk of developing Alzheimer's disease, the biological basis for such benefits from the different exercise modes remains elusive. The present ...study thus aimed (i) to investigate the effects of acute aerobic or resistance exercise on neurocognitive performances and molecular markers when performing a cognitive task involving executive functioning in older adults with amnestic mild cognitive impairment (aMCI), and (ii) to explore relationships of acute exercise-induced neurocognitive changes with changes in circulating levels of neuroprotective growth factors (e.g., BDNF, IGF-1, VEGF, and FGF-2, collectively termed ‘exerkines’), elicited by different acute exercise modes. Sixty-six older adults with aMCI were recruited and randomly assigned to an aerobic exercise (AE) group, a resistance exercise (RE) group, or a non-exercise-intervention (control) group. The behavioral i.e., accuracy rate (AR) and reaction time (RT) and electrophysiological i.e., event-related potential (ERP) P3 latency and amplitude collected from the Fz, Cz, and Pz electrodes indices were simultaneously measured when participants performed a Flanker task at baseline and after either an acute bout of 30min of moderate-intensity AE, RE or a control period. Blood samples were taken at three time points, one at baseline (T1) and two after an acute exercise intervention (T2 and T3: before and after cognitive task test, respectively). The results showed that the acute AE and RE not only improved behavioral (i.e., RTs) performance but also increased the ERP P3 amplitudes in the older adults with aMCI. Serum FGF-2 levels did not change with acute aerobic or resistance exercise. However, an acute bout of aerobic exercise significantly increased serum levels of BDNF and IGF-1 and tended to increase serum levels of VEGF in elderly aMCI individuals. Acute resistance exercise increased only serum IGF-1 levels. However, the exercise-induced elevated levels of these molecular markers returned almost to baseline levels in T3 (about 20min after acute exercise). In addition, changes in the levels of neurotrophic and angiogenic factors were not correlated with changes in RTs and P3 amplitudes. The present findings of changes in neuroprotective growth factors and neurocognitive performances through acute AE or RE suggest that molecular and neural prerequisites for exercise-dependent plasticity are preserved in elderly aMCI individuals. However, the distinct pattern of changes in circulating molecular biomarkers induced by two different exercise modes in aMCI elderly individuals and the potentially interactive mechanisms of the effects of BDNF, IGF-1, and VEGF on amyloid-β provide a basis for future long-term exercise intervention to investigate whether AE relative to RE might be more effective in prevention/treatment of an early stage neurodegenerative disease.
•Different exercise modes can induce distinct changes in serum levels of molecular biomarkers.•Aerobic and resistance exercise produce similar impacts on neurocognitive performance.•Exercise may attenuate the risks of cognitive impairment via divergent biologic pathways.•Older adults with MCI exhibit molecular and neural plasticity in response to exercise.•Physical exercise could reduce the risk of dementia/AD in the long term.
Obesity, type 2 diabetes (T2DM) and cardiovascular disease (CVD) are the most common preventable causes of morbidity and mortality worldwide. They represent major public health threat to our society. ...Increasing prevalence of obesity and T2DM contributes to escalating morbidity and mortality from CVD and stroke. Carnosine (β-alanyl-
l
-histidine) is a dipeptide with anti-inflammatory, antioxidant, anti-glycation, anti-ischaemic and chelating roles and is available as an over-the-counter food supplement. Animal evidence suggests that carnosine may offer many promising therapeutic benefits for multiple chronic diseases due to these properties. Carnosine, traditionally used in exercise physiology to increase exercise performance, has potential preventative and therapeutic benefits in obesity, insulin resistance, T2DM and diabetic microvascular and macrovascular complications (CVD and stroke) as well as number of neurological and mental health conditions. However, relatively little evidence is available in humans. Thus, future studies should focus on well-designed clinical trials to confirm or refute a potential role of carnosine in the prevention and treatment of chronic diseases in humans, in addition to advancing knowledge from the basic science and animal studies.
Activation of thermogenic brown and beige adipocytes is considered as a strategy to improve metabolic control. Here, we identify GPR180 as a receptor regulating brown and beige adipocyte function and ...whole-body glucose homeostasis, whose expression in humans is associated with improved metabolic control. We demonstrate that GPR180 is not a GPCR but a component of the TGFβ signalling pathway and regulates the activity of the TGFβ receptor complex through SMAD3 phosphorylation. In addition, using genetic and pharmacological tools, we provide evidence that GPR180 is required to manifest Collagen triple helix repeat containing 1 (CTHRC1) action to regulate brown and beige adipocyte activity and glucose homeostasis. In this work, we show that CTHRC1/GPR180 signalling integrates into the TGFβ signalling as an alternative axis to fine-tune and achieve low-grade activation of the pathway to prevent pathophysiological response while contributing to control of glucose and energy metabolism.
Recent research focusing on brown adipose tissue (BAT) function emphasizes its importance in systemic metabolic homeostasis. We show here that genetic and pharmacological inhibition of the mevalonate ...pathway leads to reduced human and mouse brown adipocyte function in vitro and impaired adipose tissue browning in vivo. A retrospective analysis of a large patient cohort suggests an inverse correlation between statin use and active BAT in humans, while we show in a prospective clinical trial that fluvastatin reduces thermogenic gene expression in human BAT. We identify geranylgeranyl pyrophosphate as the key mevalonate pathway intermediate driving adipocyte browning in vitro and in vivo, whose effects are mediated by geranylgeranyltransferases (GGTases), enzymes catalyzing geranylgeranylation of small GTP-binding proteins, thereby regulating YAP1/TAZ signaling through F-actin modulation. Conversely, adipocyte-specific ablation of GGTase I leads to impaired adipocyte browning, reduced energy expenditure, and glucose intolerance under obesogenic conditions, highlighting the importance of this pathway in modulating brown adipocyte functionality and systemic metabolism.
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•The mevalonate pathway is important for adipose tissue browning in mouse and human•Statin use is inversely correlated with brown fat activity in humans•Geranylgeranylation of small GTP-binding proteins promotes adipocyte browning•Small GTP-binding proteins regulate F-actin formation and YAP1/TAZ stability
Through genetic and pharmacological in vivo and in vitro approaches, Balaz et al. show that the mevalonate pathway is important for adipocyte browning. The importance of this pathway is supported by a retrospective clinical study and a small volunteer trial with fluvastatin. The authors identify geranylgeranyl pyrophosphate as the key mevalonate intermediate driving adipocyte browning.
Neurological, neurodegenerative, and psychiatric disorders represent a serious burden because of their increasing prevalence, risk of disability, and the lack of effective causal/disease-modifying ...treatments. There is a growing body of evidence indicating potentially favourable effects of carnosine, which is an over-the-counter food supplement, in peripheral tissues. Although most studies to date have focused on the role of carnosine in metabolic and cardiovascular disorders, the physiological presence of this di-peptide and its analogues in the brain together with their ability to cross the blood-brain barrier as well as evidence from in vitro, animal, and human studies suggest carnosine as a promising therapeutic target in brain disorders. In this review, we aim to provide a comprehensive overview of the role of carnosine in neurological, neurodevelopmental, neurodegenerative, and psychiatric disorders, summarizing current evidence from cell, animal, and human cross-sectional, longitudinal studies, and randomized controlled trials.
Objective
Carnosine is a naturally present dipeptide in humans and an over‐the counter food additive. Evidence from animal studies supports the role for carnosine in the prevention and treatment of ...diabetes and cardiovascular disease, yet there is limited human data. This study investigated whether carnosine supplementation in individuals with overweight or obesity improves diabetes and cardiovascular risk factors.
Methods
In a double‐blind randomized pilot trial in nondiabetic individuals with overweight and obesity (age 43 ± 8 years; body mass index 31 ± 4 kg/m2), 15 individuals were randomly assigned to 2 g carnosine daily and 15 individuals to placebo for 12 weeks. Insulin sensitivity and secretion, glucose tolerance (oral glucose tolerance test), blood pressure, plasma lipid profile, skeletal muscle (1H‐MRS), and urinary carnosine levels were measured.
Results
Carnosine concentrations increased in urine after supplementation (P < 0.05). An increase in fasting insulin and insulin resistance was hampered in individuals receiving carnosine compared to placebo, and this remained significant after adjustment for age, sex, and change in body weight (P = 0.02, P = 0.04, respectively). Two‐hour glucose and insulin were both lower after carnosine supplementation compared to placebo in individuals with impaired glucose tolerance (P < 0.05).
Conclusions
These pilot intervention data suggest that carnosine supplementation may be an effective strategy for prevention of type 2 diabetes.
Apart from UCP1-based nonshivering thermogenesis in brown adipocytes, the identity of thermogenic mechanisms that can be activated
to reduce a positive energy balance is largely unknown. To identify ...potentially useful mechanisms, we have analyzed physiological
and molecular mechanisms that enable mice, genetically deficient in UCP1 and sensitive to acute exposure to the cold at 4
°C, to adapt to long term exposure at 4 °C. UCP1-deficient mice that can adapt to the cold have increased oxygen consumption
and show increased oxidation of both fat and glucose as indicated from serum metabolite levels and liver glycogen content.
Enhanced energy metabolism in inguinal fat was also indicated by increased oxygen consumption and fat oxidation in tissue
suspensions and increased AMP kinase activity in dissected tissues. Analysis of gene expression in skeletal muscle showed
surprisingly little change between cold-adapted Ucp1 +/+ and Ucp1 -/- mice, whereas in inguinal fat a robust induction occurred for type 2 deiodinase, sarcoendoplasmic reticulum Ca 2+ -ATPase, mitochondrial glycerol 3-phosphate dehydrogenase, PGC1α, CoxII, and mitochondrial DNA content. Western blot analysis
showed an induction of total phospholamban and its phosphorylated form in inguinal fat and other white fat depots, but no
induction was apparent in muscle. We conclude that alternative thermogenic mechanisms, based in part upon the enhanced capacity
for ion and substrate cycling associated with brown adipocytes in white fat depots, are induced in UCP1-deficient mice by
gradual cold adaptation.
While Bmp4 has a well-established role in the commitment of mesenchymal stem cells into the adipogenic lineage, its role in brown adipocyte formation and activity is not well defined. Here, we show ...that Bmp4 has a dual function in adipogenesis by inducing adipocyte commitment while inhibiting the acquisition of a brown phenotype during terminal differentiation. Selective brown adipose tissue overexpression of Bmp4 in mice induces a shift from a brown to a white-like adipocyte phenotype. This effect is mediated by Smad signaling and might be in part due to suppression of lipolysis, via regulation of hormone sensitive lipase expression linked to reduced Ppar activity. Given that we observed a strong correlation between BMP4 levels and adipocyte size, as well as insulin sensitivity in humans, we propose that Bmp4 is an important factor in the context of obesity and type 2 diabetes.
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•Bmp4 promotes differentiation of brown pre-adipocytes into white-like adipocytes•Bmp4 blunts the activity of mature brown adipocytes•Ectopic expression of Bmp4 in brown adipose tissue reduces energy expenditure•Obese type 2 diabetic subjects have higher levels of circulating BMP4
Modica et al. show that upon commitment of mesenchymal stem cells into adipogenic lineage, Bmp4 attenuates the acquisition and maintenance of a brown phenotype by reducing lipolysis and brown fat gene expression via Smad signaling. Consequently, brown adipose tissue function is impaired.
Peroxisome proliferator-activated receptors (PPARs) have been suggested as the master regulators of adipose tissue formation. However, their role in regulating brown fat functionality has not been ...resolved. To address this question, we generated mice with inducible brown fat-specific deletions of PPARα, β/δ, and γ, respectively. We found that both PPARα and β/δδ are dispensable for brown fat function. In contrast, we could show that ablation of PPARγ in vitro and in vivo led to a reduced thermogenic capacity accompanied by a loss of inducibility by β-adrenergic signaling, as well as a shift from oxidative fatty acid metabolism to glucose utilization. We identified glycerol kinase (Gyk) as a partial mediator of PPARγ function and could show that Gyk expression correlates with brown fat thermogenic capacity in human brown fat biopsies. Thus, Gyk might constitute the link between PPARγ-mediated regulation of brown fat function and activation by β-adrenergic signaling.
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•PPARα and β/δ are dispensable for maintaining brown adipocyte function in vivo•PPARγ is needed for β-adrenergic signaling-mediated induction of brown adipocytes•Gyk, a known target of PPARγ, is a partial mediator of the effects of PPARγ•Loss of Gyk leads to regulation of PPARγ target genes by an unknown mechanism
Lasar et al. show that PPARγ is required to maintain the thermogenic capacity of mature brown adipocytes, which can be induced by activating β-adrenergic signaling. They show that expression of the known PPARγ target Gyk correlates with human brown fat activity and identify Gyk as a partial mediator of PPARγ function.
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