Summary
This systematic review aimed at addressing the ursolic acid actions as an adjunctive treatment of the obesity‐mediated metabolic abnormalities. To explore our aims, we used the literature ...search including clinical and animal studies using the Medline and Google Scholar (up to December 2015). Out of 63 screened studies, 17 presented eligibility criteria, such as the use of ursolic acid on adiposity, energy expenditure and skeletal muscle mass in mice and humans. In the literature, we found that several physiological and molecular mechanisms are implicated in the effects of ursolic acid on obesity, energy expenditure, hepatic steatosis, skeletal muscle mass loss and physical fitness, such as (1) increase of thermogenesis by modulation adipocyte transcription factors, activation of 5′ adenosine monophosphate‐activated protein kinase and overexpression of the uncoupling protein 1 thermogenic marker; (2) enhancement of skeletal muscle mass by activation in bloodstream growth hormone and insulin‐like growth factor‐1 concentrations secretion, as well as in the activation of mammalian target of rapamycin and inhibition of ring‐finger protein‐1; and (3) improvement of physical fitness by skeletal muscle proliferator‐activated receptor gamma co‐activator alpha and sirtuin 1 expression. Therefore, supplementation with ursolic acid may be an adjunctive therapy for prevention and treatment of obesity‐mediated and muscle mass‐mediated metabolic consequences.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract Obesity is a worldwide multifactorial disease caused by an imbalance in energy metabolism, increasing adiposity, weight gain, and promoting related diseases such as diabetes, cardiovascular ...diseases, neurodegeneration, and cancer. Recent findings have reported that metabolic stress related to obesity induces a mitochondrial stress response called mitochondrial unfolded protein response (UPR mt ), a quality control pathway that occurs in a nuclear DNA–mitochondria crosstalk, causing transduction of chaperones and proteases under stress conditions. The duality of UPR mt signaling, with both beneficial and detrimental effects, acts in different contexts depending on the tissue, cell type, and physiological states, affecting the mitochondrial function and efficiency and the metabolism homeostasis during obesity, which remains not fully clarified. Therefore, this review discusses the most recent findings regarding UPR mt signaling during obesity, bringing an overview of UPR mt across different metabolic tissues.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Abstract
The impairment of the mitochondrial functions is a hallmark of aging. During aging, there is a downregulation of two mechanisms strictly associated with mitochondrial integrity, including ...the mitonuclear imbalance (eg, imbalance in mitochondrial- versus nuclear-encoded mitochondrial proteins) and the mitochondrial unfolded protein response (UPRmt). Here, we evaluated the effects of aerobic exercise in the mitonuclear imbalance and UPRmt markers in the skeletal muscle of old mice. We combined the physiological tests, molecular and bioinformatic analyzes to evaluate the effects of 4 weeks of aerobic exercise training on mitonuclear imbalance and UPRmt markers in the skeletal muscle of young (2 months) and aged (24 months) C57BL/6J mice. Initially, we found that aging reduced several mitochondrial genes in the gastrocnemius muscle, and it was accompanied by the low levels of UPRmt markers, including Yme1l1 and Clpp mRNA. As expected, physical training improved the whole-body metabolism and physical performance of aged mice. The aerobic exercise increased key proteins involved in the mitochondrial biogenesis/functions (VDAC and SIRT1) along with mitochondrial-encoded genes (mtNd1, mtCytB, and mtD-Loop) in the skeletal muscle of old mice. Interestingly, aerobic exercise induced the mitonuclear imbalance, increasing MTCO1/ATP5a ratio and UPRmt markers in the skeletal muscle, including HSP60, Lonp1, and Yme1L1 protein levels in the gastrocnemius muscle of aged mice. These data demonstrate that aerobic exercise training induced mitonuclear imbalance and UPRmt in the skeletal muscle during aging. These phenomena could be involved in the improvement of the mitochondrial metabolism and oxidative capacity in aged individuals.
Alzheimer's disease (AD) is associated with peripheral metabolic disorders. Clinical/epidemiological data indicate increased risk of diabetes in AD patients. Here, we show that ...intracerebroventricular infusion of AD‐associated Aβ oligomers (AβOs) in mice triggered peripheral glucose intolerance, a phenomenon further verified in two transgenic mouse models of AD. Systemically injected AβOs failed to induce glucose intolerance, suggesting AβOs target brain regions involved in peripheral metabolic control. Accordingly, we show that AβOs affected hypothalamic neurons in culture, inducing eukaryotic translation initiation factor 2α phosphorylation (eIF2α‐P). AβOs further induced eIF2α‐P and activated pro‐inflammatory IKKβ/NF‐κB signaling in the hypothalamus of mice and macaques. AβOs failed to trigger peripheral glucose intolerance in tumor necrosis factor‐α (TNF‐α) receptor 1 knockout mice. Pharmacological inhibition of brain inflammation and endoplasmic reticulum stress prevented glucose intolerance in mice, indicating that AβOs act via a central route to affect peripheral glucose homeostasis. While the hypothalamus has been largely ignored in the AD field, our findings indicate that AβOs affect this brain region and reveal novel shared molecular mechanisms between hypothalamic dysfunction in metabolic disorders and AD.
Synopsis
Centrally administered Aβ oligomers can trigger insulin resistance by engaging ER stress and inflammatory signals in the central nervous system. This study provides important insights into the link between Alzheimer's disease and diabetes by pointing to a common etiology.
Aβ oligomers (ΑβOs), toxins that accumulate in the AD brain and have been linked to neuronal dysfunction in brain areas related to learning and memory, impact the hypothalamus of mice and macaques, revealing a novel toxic mechanism of AβOs in the brain.
Infusion of AβOs in the brain triggers peripheral glucose intolerance, insulin resistance and other diabetes‐related metabolic alterations in mice. Similar metabolic alterations were verified in two transgenic mouse models of AD.
Blockade of brain inflammation or ER stress attenuates peripheral glucose intolerance induced by brain infusion of AβOs, suggesting that AβOs use a central route to disrupt metabolic control in peripheral tissues.
Current results may explain why AD patients have increased risk of developing diabetes, and suggest that targeting the hypothalamus may constitute an approach to combat peripheral metabolic deregulation in AD.
Centrally administered Aβ oligomers can trigger insulin resistance by engaging ER stress and inflammatory signals in the central nervous system. This study provides important insights into the link between Alzheimer's disease and diabetes by pointing to a common etiology.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Sestrins and autophagy deficiencies are associated with several aging-related organic dysfunctions and metabolic disorders. Here we evaluate the effects of acute exercise on Sestrin 2 (Sesn2) protein ...content and autophagy markers in the skeletal muscle of experimental models of aging. Twenty-four months-old C57BL/6J male mice were submitted to a single bout of swimming exercise and the gastrocnemius muscle was evaluated by Western blot. Transcriptomic and phenotypic analysis were also performed by using strains of genetically-diverse BXD mice. The bioinformatics analysis showed a negative correlation between Sesn2 mRNA levels in the skeletal muscle and body weight gain, plasma triglycerides and fasting glucose and positive correlation with several autophagic markers in the muscle of BXD mice. Consistent with these findings, low levels of Sesn2 protein content were observed in the gastrocnemius muscle of C57BL/6J old mice when compared to young group. Interestingly, the acute aerobic exercise induced Sesn2 accumulation and modulated several markers of autophagy in the gastrocnemius muscle old mice, including unc-51-like kinase-1 (Ulk1) phosphorylation and the protein levels of Atg5, Atg7, p62 and LC3-II. Finally, exercise increased insulin sensitivity in old animals, as demonstrated by kITT. Taken together, these findings demonstrated the acutely, aerobic physical exercise recovers Sestrin 2 protein content and induces autophagy in the skeletal muscle of old mice, contributing with the improvement of insulin sensitivity an aging animal model.
•Downregulation of Sestrin2 in the skeletal muscle of old mice.•Exercise stimulates Sestrin2 accumulation in the skeletal muscle of old mice.•Physical exercise elicits autophagy in the skeletal muscle of old mice.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Sphingosine 1-phosphate receptor 1 (S1PR1) is a G-protein-coupled receptor for sphingosine-1-phosphate (S1P) that has a role in many physiological and pathophysiological processes. Here we show that ...the S1P/S1PR1 signalling pathway in hypothalamic neurons regulates energy homeostasis in rodents. We demonstrate that S1PR1 protein is highly enriched in hypothalamic POMC neurons of rats. Intracerebroventricular injections of the bioactive lipid, S1P, reduce food consumption and increase rat energy expenditure through persistent activation of STAT3 and the melanocortin system. Similarly, the selective disruption of hypothalamic S1PR1 increases food intake and reduces the respiratory exchange ratio. We further show that STAT3 controls S1PR1 expression in neurons via a positive feedback mechanism. Interestingly, several models of obesity and cancer anorexia display an imbalance of hypothalamic S1P/S1PR1/STAT3 axis, whereas pharmacological intervention ameliorates these phenotypes. Taken together, our data demonstrate that the neuronal S1P/S1PR1/STAT3 signalling axis plays a critical role in the control of energy homeostasis in rats.
Hypothalamic inflammation is associated with insulin and leptin resistance, hyperphagia, and obesity. In this scenario, hypothalamic protein tyrosine phosphatase 1B (PTP1B) has emerged as the key ...phosphatase induced by inflammation that is responsible for the central insulin and leptin resistance. Here, we demonstrated that acute exercise reduced inflammation and PTP1B protein level/activity in the hypothalamus of obese rodents. Exercise disrupted the interaction between PTP1B with proteins involved in the early steps of insulin (IRβ and IRS-1) and leptin (JAK2) signaling, increased the tyrosine phosphorylation of these molecules, and restored the anorexigenic effects of insulin and leptin in obese rats. Interestingly, the anti-inflammatory action and the reduction of PTP1B activity mediated by exercise occurred in an interleukin-6 (IL-6)-dependent manner because exercise failed to reduce inflammation and PTP1B protein level after the disruption of hypothalamic-specific IL-6 action in obese rats. Conversely, intracerebroventricular administration of recombinant IL-6 reproduced the effects of exercise, improving hypothalamic insulin and leptin action by reducing the inflammatory signaling and PTP1B activity in obese rats at rest. Taken together, our study reports that physical exercise restores insulin and leptin signaling, at least in part, by reducing hypothalamic PTP1B protein level through the central anti-inflammatory response.
Hypothalamic sphingosine‐1‐phosphate receptor 1 (S1PR1), the G protein–coupled receptor 1 of sphingosine‐1‐phosphate, has been described as a modulator in the control of energy homeostasis in ...rodents. However, this mechanism is still unclear. Here, we evaluate the role of interleukin 6 (IL‐6) associated with acute physical exercise in the control of the hypothalamic S1PR1–signal transducer and activator of transcription 3 (STAT3) axis. Acute exercise session and an intracerebroventricular IL‐6 injection increased S1PR1 protein content and STAT3 phosphorylation in the hypothalamus of lean and obese mice accompanied by a reduction in food consumption. Transcriptome analysis indicated a strong positive correlation between Il‐6 and S1pr1 messenger RNA in several tissues of genetically diverse BXD mice strains and humans, including in the hypothalamus. Interestingly, exercise failed to stimulate the S1PR1–STAT3 axis in IL‐6 knockout mice and the disruption of hypothalamic‐specific IL‐6 action blocked the anorexigenic effects of exercise. Taken together, our results indicate that physical exercise modulates the S1PR1 protein content in the hypothalamus, through the central action of IL‐6.
Exercise, hypothalamic sphingosine‐1‐phosphate receptor 1, interleukin 6, and hypothalamus.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Obesity and aging lead to abnormal transforming growth factor‐β1 (TGF‐β1) signaling in the hypothalamus, triggering the imbalance on glucose metabolism and energy homeostasis. Here, we determine the ...effect of acute exercise on TGF‐β1 expression in the hypothalamus of two models of obesity in mice. The bioinformatics analysis was performed to evaluate the correlation between hypothalamic Tgf‐β1 messenger RNA (mRNA) and genes related to thermogenesis in the brown adipose tissue (BAT) by using a large panel of isogenic BXD mice. Thereafter, leptin‐deficient (ob/ob) mice and obese C57BL/6 mice fed on a high‐fat diet (HFD) were submitted to the acute exercise protocol. Transcriptomic analysis by using BXD mouse reference population database revealed that hypothalamic Tgf‐β1 mRNA is negatively correlated with genes related to thermogenesis in brown adipose tissue of BXD mice, such as peroxisome proliferator‐activated receptor gamma coactivator and is positively correlated with respiratory exchange ratio. In agreement with these results, leptin‐deficient (ob/ob) and HFD‐fed mice displayed high levels of Tgf‐β1 mRNA in the hypothalamus and reduction of Pgc1α mRNA in BAT. Interestingly, an acute exercise session reduced TGF‐β1 expression in the hypothalamus, increased Pgc1α mRNA in the BAT and reduced food consumption in obese mice. Our results demonstrated that acute physical exercise suppressed hypothalamic TGF‐β1 expression, increasing Pgc1α mRNA in BAT in obese mice.
Obesity conditions increased transforming growth factor‐β1 (TGF‐β1) messenger RNA in the hypothalamus of obese mice; acute exercise reduces TGF‐β1 protein content and decreased food consumption in obese mice.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Accumulating evidence has demonstrated that S-nitrosation of proteins plays a critical role in several human diseases. Here, we explored the role of inducible nitric oxide synthase (iNOS) in the ...S-nitrosation of proteins involved in the early steps of the insulin-signaling pathway and insulin resistance in the skeletal muscle of aged mice. Aging increased iNOS expression and S-nitrosation of major proteins involved in insulin signaling, thereby reducing insulin sensitivity in skeletal muscle. Conversely, aged iNOS-null mice were protected from S-nitrosation-induced insulin resistance. Moreover, pharmacological treatment with an iNOS inhibitor and acute exercise reduced iNOS-induced S-nitrosation and increased insulin sensitivity in the muscle of aged animals. These findings indicate that the insulin resistance observed in aged mice is mainly mediated through the S-nitrosation of the insulin-signaling pathway.
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