TCPTP-deficiency in muscle does not alter insulin signalling and glucose homeostasis.

Aims/Hypothesis: Insulin activates the insulin receptor (IR) protein tyrosine kinase and downstream phosphatidylinositol-3-kinase (PI3K)/Akt signalling in muscle to promote glucose uptake. The IR can serve as a substrate for the protein tyrosine phosphatases (PTP) 1B and TCPTP, which share a striking 74% sequence identity in their catalytic domains. PTP1B is a validated therapeutic target for the alleviation of insulin resistance in type 2 diabetes. PTP1B dephosphorylates the IR in liver and muscle to regulate glucose homeostasis, whereas TCPTP regulates IR signalling and gluconeogenesis in the liver. In this study we have assessed for the first time the role of TCPTP in the regulation of IR signalling in muscle. Methods: We generated muscle-specific TCPTP-deficient (MCK-Cre;Ptpn2lox/lox) mice and assessed the impact on glucose homeostasis and muscle IR signalling in chow versus high fat fed mice. Results: Blood glucose and insulin levels, insulin and glucose tolerances and insulininduced muscle IR activation and downstream PI3K/Akt signalling remained unaltered in chow fe

He Rourou Whai Painga, an Aotearoa New Zealand dietary pattern for metabolic health and whānau wellbeing: protocol for a randomized controlled trial

BackgroundCardiometabolic diseases are highly prevalent in Aotearoa New Zealand. Dietary intake is a modifiable risk factor for such diseases and certain dietary patterns, specifically the Mediterranean diet (MedDiet), are associated with improved metabolic health. This study aims to test whether an intervention including a Mediterranean dietary pattern incorporating high quality New Zealand foods (NZMedDiet pattern) and behavior change science can improve the metabolic health of participants and their household/whānau.Methods and analysisThis is a multi-center, three-stage trial with two parallel group superiority randomized controlled trials (RCTs), and a longitudinal cohort study embedded within the trial design. The first RCT (RCT 1) is a comparison of the NZMedDiet pattern compared to usual diet for 12 weeks. The Behavior Change Wheel was used to select and implement strategies to support participant adherence to the NZMedDiet, such as web-based nutrition education on healthy shopping and cooking. The second (RCT 2) compares online social support to no online social support for 12 weeks, administered to participants immediately following RCT 1. The third stage is a longitudinal cohort study where all participants are followed from the beginning of their start of the active intervention for 12 months in total. The primary outcome measure for each stage is the metabolic syndrome severity score (MetSSS). The duration of enrolment is 12–15 months. The total recruitment target is 200 index participants and their household/whānau members who participate with them, and the primary analyses will be intention to treat on index participants.DiscussionThe trial will test whether the NZMedDiet pattern and behavior change support improves the cardiometabolic health of people in Aotearoa New Zealand.Clinical trial registrationhttps://www.anzctr.org.au/Default.aspx, identifier ACTRN12622000906752 and https://www.isrctn.com/, identifier ISRCTN89011056 (Spirit 2)

Leptin and Insulin Act on POMC Neurons to Promote the Browning of White Fat

SummaryThe primary task of white adipose tissue (WAT) is the storage of lipids. However, “beige” adipocytes also exist in WAT. Beige adipocytes burn fat and dissipate the energy as heat, but their abundance is diminished in obesity. Stimulating beige adipocyte development, or WAT browning, increases energy expenditure and holds potential for combating metabolic disease and obesity. Here, we report that insulin and leptin act together on hypothalamic neurons to promote WAT browning and weight loss. Deletion of the phosphatases PTP1B and TCPTP enhanced insulin and leptin signaling in proopiomelanocortin neurons and prevented diet-induced obesity by increasing WAT browning and energy expenditure. The coinfusion of insulin plus leptin into the CNS or the activation of proopiomelanocortin neurons also increased WAT browning and decreased adiposity. Our findings identify a homeostatic mechanism for coordinating the status of energy stores, as relayed by insulin and leptin, with the central control of WAT browning

Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance

Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance. Conversely, reductions in skeletal muscle NOX4 in aging and obesity contribute to the development of insulin resistance. NOX4 deletion in skeletal muscle compromised exercise capacity and antioxidant defense and promoted oxidative stress and insulin resistance in aging and obesity. The abrogated adaptive mechanisms, oxidative stress, and insulin resistance could be corrected by deleting the H2O2-detoxifying enzyme GPX-1 or by treating mice with an agonist of NFE2L2, the master regulator of antioxidant defense. These findings causally link NOX4-derived ROS in skeletal muscle with adaptive responses that promote muscle function and insulin sensitivity

The role of reactive oxygen species and nitric oxide in the regulation of skeletal muscle glucose uptake during contraction

© 2010 Dr. Troy L. MerryThere is evidence that reactive oxygen species (ROS) and nitric oxide (NO) are involved in the regulation of skeletal muscle glucose uptake during contraction. This thesis examined the role of ROS in regulating skeletal muscle glucose uptake during contractions ex vivo and in situ in rodents and during in vivo exercise in humans and the potential downstream mechanisms through which NO signals skeletal muscle glucose uptake during contractions ex vivo. Since there has been some evidence that both ROS and NO may signal through AMPK, the relationships between NO, ROS and AMPK with contraction were examined. Isolated muscles from mice that express a muscle specific kinase dead AMPKα2 isoform (AMPK KD) were stimulated to contract ex vivo. Despite no increases in AMPK activity, muscles (soleus and extensor digitorum longus; EDL) from AMPK KD mice showed normal contraction-stimulated increases in glucose uptake which was attenuated by the antioxidant N-acetylcysteine (NAC) and the NOS inhibitor NG-Monomethyl-L-Arginine (L-NMMA) to a similar extent as in muscles of wild type mice. Furthermore, the co-treatment of EDL muscles from C57Bl/6 mice with L-NMMA and NAC did not have an additive effect on the attenuation of skeletal muscle glucose uptake during contraction. These results indicate that ROS and NO are involved in regulating skeletal muscle glucose uptake during contractions ex vivo, through a similar pathway that is independent of AMPK. To examine the downstream mechanisms through which NO regulates glucose uptake, EDL muscles from C57Bl/6 mice were contracted ex vivo in the presence and absence of inhibitors of potential NO signalling intermediates. In contrast to NOS inhibition with L-NMMA, the inhibition of soluble guanylate cyclase (sGC; which prevents the formation of cGMP) and PKG (cGMP dependent protein kinase) did not affect skeletal muscle glucose uptake during contraction. This suggests that during contraction NO regulates skeletal muscle glucose uptake through a cGMP-PKG independent pathway. To investigate alternative mechanisms through which NO regulates skeletal muscle glucose uptake during contraction, while light was used to prevent S-nitrosylation, and the antioxidants urate and DTT were used to scavenge peroxynitrite and prevent protein S-glutathionylation, respectively. It was found that urate and DTT, but not white light, attenuated contraction-stimulated increases in skeletal muscle glucose uptake. Furthermore, like L-NMMA and NAC, DTT and urate attenuated contraction-stimulated increases in S-glutathionylation and tyrosine nitration of a protein band at ~37 kDa. This suggests that during contractions ex vivo, NO and ROS regulate glucose uptake through a similar pathway that may involve signalling through peroxynitrite and/or S-glutathionylation. The results of these ex vivo studies suggest that ROS are regulating skeletal muscle glucose uptake during contraction, perhaps via a similar mechanism(s) as NO. To examine this further in more physiological models, NAC was infused locally into the hindlimb of rats contracted in situ and systemically in humans during exercise. Surprisingly, NAC did not affect the increase in glucose uptake during hindlimb contractions in situ in rats, or the increase in glucose disposal during exercise in humans. It is possible the discrepancy between results obtained in ex vivo preparations and the in situ and in vivo models is related to an unphysiological increases in ROS in ex vivo preparations as a result of supramaximal contraction protocols, non-uniform delivery of oxygen to muscle fibres, hyperoxic incubation medium and an absence of antioxidant systems surrounding muscle (such as that supplied by blood flow). Therefore, the findings of this thesis provide evidence that ROS and NO regulate skeletal muscle glucose uptake during contractions ex vivo through a similar pathway that is independent of AMPK and cGMP/PKG, but may involve signalling through peroxynitrite and/or S-glutathionylation. However, unlike our previous observations in regards to NO, ROS do not appear to be essential for the regulation of skeletal muscle glucose uptake during moderate intensity contractions/exercise in intact physiological preparations

Do reactive oxygen species regulate skeletal muscle glucose uptake during contraction?

This review examines the evidence for ROS as signaling intermediates in the regulation of skeletal muscle glucose uptake during contraction. It is important to highlight that the pathway through which contraction regulates skeletal muscle glucose uptake differs from that of insulin-stimulated glucose uptake (20) and that ROS, in particular H2O2, also are implicated in the regulation of insulin-stimulated glucose uptake (33)

The rise of genetically engineered mouse models of pancreatitis: A review of literature

Pancreatitis is increasingly recognized as not merely a local inflammation of the pancreas but also a disease with high frequency of systemic sequelae. Current understanding of the cellular mechanisms that trigger it and affect the development of sequelae are limited. Genetically engineered mouse models can be a useful tool to study the pathophysiology of pancreatitis. This article gives an overview of the genetically engineered mouse models that spontaneously develop pancreatitis and discusses those that most closely replicate different pancreatitis hallmarks observed in humans

Mitochondria-Targeted Antioxidants and Skeletal Muscle Function

One of the main sources of reactive oxygen species (ROS) in skeletal muscle is the mitochondria. Prolonged or very high ROS exposure causes oxidative damage, which can be deleterious to muscle function, and as such, there is growing interest in targeting antioxidants to the mitochondria in an effort to prevent or treat muscle dysfunction and damage associated with disease and injury. Paradoxically, however, ROS also act as important signalling molecules in controlling cellular homeostasis, and therefore caution must be taken when supplementing with antioxidants. It is possible that mitochondria-targeted antioxidants may limit oxidative stress without suppressing ROS from non-mitochondrial sources that might be important for cell signalling. Therefore, in this review, we summarise literature relating to the effect of mitochondria-targeted antioxidants on skeletal muscle function. Overall, mitochondria-targeted antioxidants appear to exert beneficial effects on mitochondrial capacity and function, insulin sensitivity and age-related declines in muscle function. However, it seems that this is dependent on the type of mitochondrial-trageted antioxidant employed, and its specific mechanism of action, rather than simply targeting to the mitochondria

Local hindlimb antioxidant infusion does not affect muscle glucose uptake during in situ contractions in rat

There is evidence that reactive oxygen species (ROS) contribute to the regulation of skeletal muscle glucose uptake during highly fatiguing ex vivo contraction conditions via AMP-activated protein kinase (AMPK). In this study we investigated the role of ROS in the regulation of glucose uptake and AMPK signaling during low-moderate intensity in situ hindlimb muscle contractions in rats, which is a more physiological protocol and preparation. Male hooded Wistar rats were anesthetized, and then N-acetylcysteine (NAC) was infused into the epigastric artery (125 mg·kg−1·h−1) of one hindlimb (contracted leg) for 15 min before this leg was electrically stimulated (0.1-ms impulse at 2 Hz and 35 V) to contract at a low-moderate intensity for 15 min. The contralateral leg did not receive stimulation or local NAC infusion (rest leg). NAC infusion increased (P < 0.05) plasma cysteine and cystine (by ∼360- and 1.4-fold, respectively) and muscle cysteine (by 1.5-fold, P = 0.001). Although contraction did not significantly alter muscle tyrosine nitration, reduced (GSH) or oxidized glutathione (GSSG) content, S-glutathionylation of protein bands at ∼250 and 150 kDa was increased (P < 0.05) ∼1.7-fold by contraction, and this increase was prevented by NAC. Contraction increased (P < 0.05) skeletal muscle glucose uptake 20-fold, AMPK phosphorylation 6-fold, ACCβ phosphorylation 10-fold, and p38 MAPK phosphorylation 60-fold, and the muscle fatigued by ∼30% during contraction and NAC infusion had no significant effect on any of these responses. This was despite NAC preventing increases in S-glutathionylation with contraction. In conclusion, unlike during highly fatiguing ex vivo contractions, local NAC infusion during in situ low-moderate intensity hindlimb contractions in rats, a more physiological preparation, does not attenuate increases in skeletal muscle glucose uptake or AMPK signaling

Deficiency in ROS-sensing nuclear factor erythroid 2-like 2 causes altered glucose and lipid homeostasis following exercise training

ISSN:1522-1563ISSN:0363-614