Improved glucose homeostasis in mice overexpressing human UCP3: a role for AMP-kinase?

Schrauwen, Patrick; Hardie, D. Grahame; Roorda, Berber D.; Clapham, John C.; Abuin, Alejandro; Thomason-Hughes, Michaela; Green, K; Frederik, Peter M.; Hesselink, Matthijs K. C.

doi:10.1038/sj.ijo.0802629

Cited by 38 publications

(35 citation statements)

References 24 publications

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“…Collectively, these adaptive changes also indicate the possibility of improved glucose uptake and terminal oxidation and thus highlight the utility of TNMS as a viable treatment for individuals who suffer from type 2 diabetes. It seems reasonable that TNMS should upregulate AMPK signaling capacity and efficiency and, in parallel, reduce lipid toxicity and increase the capacity for terminal substrate oxidation (46,55,64). Such a reduction would lead to improved glucose tolerance and insulin sensitivity in type 2 diabetics, similar to those reported in the ZDF rat after exercise training (52).…”

Section: Discussionsupporting

confidence: 58%

α-Catalytic subunits of 5′AMP-activated protein kinase display fiber-specific expression and are upregulated by chronic low-frequency stimulation in rat muscle

Putman

Martins²,

Gallo³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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activated protein kinase (AMPK) signaling initiates adaptive changes in skeletal muscle fibers that restore homeostatic energy balance. The purpose of this investigation was to examine, in rats, the fiber-type protein expression patterns of the ␣-catalytic subunit isoforms in various skeletal muscles, and changes in their respective contents within the tibialis anterior (TA) after chronic low-frequency electrical stimulation (CLFS; 10 Hz, 10 h daily), applied for 4 Ϯ 1.2 or 25 Ϯ 4.8 days. Immunocytochemical staining of soleus (SOL) and medial gastrocnemius (MG) showed that 86 Ϯ 4.1 to 97 Ϯ 1.4% of type IIA fibers stained for both the ␣1-and ␣2-isoforms progressively decreased to 63 Ϯ 12.2% of type IID/X and 9 Ϯ 2.4% of IIB fibers. 39 Ϯ 11.4% of IID/X and 83 Ϯ 7.9% of IIB fibers expressed only the ␣2 isoform in the MG, much of which was localized within nuclei. ␣1 and ␣2 contents, assessed by immunoblot, were lowest in the white gastrocnemius [WG; 80% myosin heavy chain (MHC) IIb; 20% MHCIId/x]. Compared with the WG, ␣1 content was 1.6 Ϯ 0.08 (P Ͻ 0.001) and 1.8 Ϯ 0.04 (P Ͻ 0.0001)-fold greater in the red gastrocnemius (RG: 13%, MHCIIa) and SOL (21%, MHCIIa), respectively, and increased in proportion to MHCIIa content. Similarly, ␣2 content was 1.4 Ϯ 0.10 (P Ͻ 0.02) and 1.5 Ϯ 0.07 (P Ͻ 0.001)-fold greater in RG and SOL compared with WG. CLFS induced 1.43 Ϯ 0.13 (P Ͻ 0.007) and 1.33 Ϯ 0.08 (P Ͻ 0.009)-fold increases in the ␣1 and ␣2 contents of the TA and coincided with the transition of faster type IIB and IID/X fibers toward IIA fibers. These findings indicate that fiber types differ with regard to their capacity for AMPK signaling and that this potential is increased by CLFS. myosin heavy chain; fast-twitch muscle; slow-twitch muscle 5Ј-AMP-ACTIVATED PROTEIN KINASE (AMPK) is a heterotrimeric serine/threonine kinase comprising an ␣ catalytic subunit (␣1 or ␣2), and noncatalytic ␤ (␤1 or ␤2) and ␥ (␥1, ␥2, or ␥3) subunits (12,41). This enzyme complex is the central component of a signaling cascade in skeletal muscle that serves as an intracellular energy-sensor by detecting decreases in the intracellular energy potential (i.e., ATP/ADP free ) through related increases in AMP (11,13,26). Being highly sensitive to small reductions in ATP and corresponding increases in AMP (25), AMPK is activated in skeletal muscle during contractile activity (32, 68, 69) to acutely restore energy balance by increasing flux through ATP-generating pathways (24, 25).In contrast, chronic AMPK activation induced by pharmacological agonists (3, 29, 58, 71) regulates long-term adaptive changes similar to exercise training that seem to limit future reductions in the intracellular energy potential and reportedly reduce metabolic disturbances in rats displaying skeletal muscle insulin resistance (9,52,70). Prolonged AMPK activation has, for example, been associated with mitochondrial genesis (3,58,71,74) and greater expression levels of genes involved in glucose uptake and storage (3, 9, 29), as well as lower plasma free fatty acid and trigl...

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Section: Discussionsupporting

confidence: 58%

α-Catalytic subunits of 5′AMP-activated protein kinase display fiber-specific expression and are upregulated by chronic low-frequency stimulation in rat muscle

Putman

Martins²,

Gallo³

et al. 2007

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Finally, we propose that these data enhance our understanding of how the mitochondria function as a cellular rheostat balancing cellular prosurvival and cell death homeostatic programs. However, it should be noted that the roles of the various mitochondrial uncoupling protein homologues are still being investigated and have a multitude of metabolic and signaling effects, (22,37,38) that have not been investigated in this study but may contribute to their role in cellular protection.…”

Section: Discussionmentioning

confidence: 99%

Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia

McLeod

Aziz

Hoyt

et al. 2005

Journal of Biological Chemistry

139

108

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Transient cardiac ischemia activates cell survival signaling, conferring subsequent ischemia tolerance to the heart. This biological phenomenon, termed ischemic preconditioning, results in improved clinical outcome and attenuated infarct size following myocardial infarction. To explore genomic modifications underpinning this ischemia tolerance, we delineated the regulation and function of the cardiac enriched mitochondrial uncoupling proteins 2 and 3 during delayed ischemic preconditioning in the rat. Cardiac transcripts of genes encoding uncoupling proteins 2 and 3 are upregulated in parallel with infarct size reduction in preconditioned hearts. Mitochondria isolated from preconditioned hearts exhibit an augmented inducible proton leak. In parallel, following anoxiareoxygenation these mitochondria generate less hydrogen peroxide compared with non-preconditioned mitochondria. Preconditioning in rat cardiac derived myoblasts is abolished following uncoupling protein-2 depletion by RNA-interference. RNAi of uncoupling protein-3 partially attenuates the capacity to precondition these cells. Functional characterization of anoxia and reoxygenation tolerance following uncoupling protein 2 or 3 and combined 2 and 3 RNAi shows the largest reduction in viability follows depletion of both homologues. Uncoupling protein-2 depletion alone significantly attenuates anoxia-reoxygenation tolerance but uncoupling protein-3 depletion does not reduce anoxia tolerance. In parallel combined uncoupling protein depletion and isolated uncoupling protein-2 depletion augments ROS production in viable cardiomyocytes following anoxia-reoxygenation. Concurrent antioxidant administration ameliorates the uncoupling protein-depleted anoxia-susceptible phenotype. In conclusion, mitochondrial uncoupling proteins are necessary components of ischemia tolerance and function as components of the cellular antioxidant defense program. In the cytoprotective hierarchy, uncoupling protein-2 appears to play a greater role than uncoupling protein-3 in modulating ischemia/anoxia tolerance in heart-derived cells.The cell survival program, termed ischemic preconditioning, evoked by transient nonlethal tissue ischemia, is evolutionarily conserved and is evident across multiple organs/tissues. The signal transduction networks engendering this phenomenon are well described (1); however, functional cellular modifications conferring ischemia tolerance are less tangible. Interestingly, the invariable metabolic signature of preconditioned tissue is enhanced capacity to restore mitochondrial function and ATP production following an ischemic insult (2). The mechanistic links between the molecular adaptations of the mitochondrion and the preconditioning cell survival program require further characterization. Further credence to the importance of mitochondrial adaptation to preconditioning-induced cell survival has been shown by improved mitochondrial respiratory and bioenergetic recovery following anoxia and reoxygenation in mitochondria extracted from ischemic, genomi...

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“…Improvements in glucose homeostasis have been achieved by overexpression of either GLUT4 or uncoupling protein 3 in skeletal muscle of mice (25,32). AMPK activation by AICAR treatment can also improve glucose homeostasis in rodents (5,7).…”

Section: Discussionmentioning

confidence: 99%

“…DAG and ceramide content were determined in gastrocnemius muscle from 4-h fasted mice by conversion of DAG and ceramides to phosphorylation products by externally added DAG kinase from Escherichia coli (Enzo Life Sciences, Farmingdale, NY) in the presence of [g- 32 P] ATP as previously described (31).…”

Section: Dag and Ceramide Contentmentioning

confidence: 99%

Effects of AMPK Activation on Insulin Sensitivity and Metabolism in Leptin-Deficient ob/ob Mice

et al. 2014

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AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (a) and two regulatory subunits (b and g), which act as a metabolic sensor to regulate glucose and lipid metabolism. A mutation in the g 3 subunit (AMPKg 3 R225Q) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKg 3 R225Q (g 3 R225Q ) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle-specific expression of AMPKg 3 R225Q prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-g 3 R225Q ) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-g 3 R225Q mice, whereas glucose tolerance was unaltered. Insulinstimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean g 3 R225Q mice, but not in ob/ob-g 3 R225Q mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from g 3 R225Q mutant mice independent of adiposity. Glycogen and triglyceride content were decreased after leptin treatment (5 days) in ob/ob mice, but not in ob/ob-g 3 R225Q mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKg 3 R225Q are insufficient to ameliorate insulin resistance and obesity in leptin-deficient mice. Central defects due to leptin deficiency may override any metabolic benefit conferred by peripheral overexpression of the AMPKg 3 R225Q mutation.

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Improved glucose homeostasis in mice overexpressing human UCP3: a role for AMP-kinase?

Cited by 38 publications

References 24 publications

α-Catalytic subunits of 5′AMP-activated protein kinase display fiber-specific expression and are upregulated by chronic low-frequency stimulation in rat muscle

α-Catalytic subunits of 5′AMP-activated protein kinase display fiber-specific expression and are upregulated by chronic low-frequency stimulation in rat muscle

Uncoupling Proteins 2 and 3 Function in Concert to Augment Tolerance to Cardiac Ischemia

Effects of AMPK Activation on Insulin Sensitivity and Metabolism in Leptin-Deficient ob/ob Mice

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