A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner

Activation of AMP-activated protein kinase (AMPK) is considered a valid strategy for the treatment of type 2 diabetes. However, despite the importance of adipose tissue for whole-body energy homeostasis, the effect of AMPK activation in adipocytes has only been studied to a limited extent and mainly with the AMP-mimetic 5-aminoimidazole-4-carboxamide-1-β-d-ribofuranoside (AICAR), which has limited specificity. The aim of this study was to evaluate the effect of the allosteric AMPK activators A-769662 and 991 on glucose uptake in adipocytes. For this purpose, primary rat or human adipocytes, and cultured 3T3-L1 adipocytes, were treated with either of the allosteric activators, or AICAR, and basal and insulin-stimulated glucose uptake was assessed. Additionally, the effect of AMPK activators on insulin-stimulated phosphorylation of Akt and Akt substrate of 160 kDa was assessed. Furthermore, primary adipocytes from ADaM site binding drug-resistant AMPKβ1 S108A knock-in mice were employed to investigate the specificity of the drugs for the observed effects. Our results show that insulin-stimulated adipocyte glucose uptake was significantly reduced by A-769662 but not 991, yet neither activator had any clear effects on basal or insulin-stimulated Akt/AS160 signaling. The use of AMPKβ1 S108A mutant-expressing adipocytes revealed that the observed inhibition of glucose uptake by A-769662 is most likely AMPK-independent, a finding which is supported by the rapid inhibitory effect A-769662 exerts on glucose uptake in 3T3-L1 adipocytes. These data suggest that AMPK activation per se does not inhibit glucose uptake in adipocytes and that the effects of AICAR and A-769662 are AMPK-independent.

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Exercise and MEF2–HDAC interactions

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-082 ◽

2007 ◽

Vol 32 (5) ◽

pp. 852-856 ◽

Cited By ~ 21

Author(s):

Sean L. McGee

Keyword(s):

Skeletal Muscle ◽

Protein Kinase ◽

Nuclear Export ◽

Energy Homeostasis ◽

Whole Body ◽

Positive Health ◽

Exercise Induced ◽

Amp Activated Protein Kinase ◽

Body Energy ◽

Skeletal Muscle Adaptations

Exercise increases the metabolic capacity of skeletal muscle, which improves whole-body energy homeostasis and contributes to the positive health benefits of exercise. This is, in part, mediated by increases in the expression of a number of metabolic enzymes, regulated largely at the level of transcription. At a molecular level, many of these genes are regulated by the class II histone deacetylase (HDAC) family of transcriptional repressors, in particular HDAC5, through their interaction with myocyte enhancer factor 2 transcription factors. HDAC5 kinases, including 5′-AMP-activated protein kinase and protein kinase D, appear to regulate skeletal muscle metabolic gene transcription by inactivating HDAC5 and inducing HDAC5 nuclear export. These mechanisms appear to participate in exercise-induced gene expression and could be important for skeletal muscle adaptations to exercise.

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Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00571.2013 ◽

2014 ◽

Vol 306 (7) ◽

pp. E769-E778 ◽

Cited By ~ 25

Author(s):

N. M. Harder-Lauridsen ◽

R. Krogh-Madsen ◽

J. J. Holst ◽

P. Plomgaard ◽

L. Leick ◽

...

Keyword(s):

Type 2 Diabetes ◽

Glucose Metabolism ◽

Glucose Uptake ◽

Whole Body ◽

Cytokine Signaling ◽

Contributing Factors ◽

Stat3 Phosphorylation ◽

Socs3 Expression ◽

Body Energy

Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [ n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m2, HbA1c7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 ( P < 0.001), neutrophils ( P < 0.001), and cortisol ( P < 0.001) increased while lymphocytes decreased ( P < 0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle ( P = 0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake ( P < 0.01) and expired carbon dioxide ( P < 0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis and previous findings in young, healthy men.

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Skeletal muscle AMP-activated protein kinase γ1H151R overexpression enhances whole body energy homeostasis and insulin sensitivity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00195.2015 ◽

2015 ◽

Vol 309 (7) ◽

pp. E679-E690 ◽

Cited By ~ 10

Author(s):

Milena Schönke ◽

Martin G. Myers ◽

Juleen R. Zierath ◽

Marie Björnholm

Keyword(s):

Skeletal Muscle ◽

Insulin Sensitivity ◽

Protein Kinase ◽

Transgenic Mice ◽

Energy Homeostasis ◽

Whole Body ◽

Α Subunit ◽

Peripheral Tissues ◽

Amp Activated Protein Kinase ◽

Body Energy

AMP-activated protein kinase (AMPK) is a major sensor of energy homeostasis and stimulates ATP-generating processes such as lipid oxidation and glycolysis in peripheral tissues. The heterotrimeric enzyme consists of a catalytic α-subunit, a β-subunit that is important for enzyme activity, and a noncatalytic γ-subunit that binds AMP and activates the AMPK complex. We generated a skeletal muscle Cre-inducible transgenic mouse model expressing a mutant γ1-subunit (AMPKγ1H151R), resulting in chronic AMPK activation. The expression of the predominant AMPKγ3 isoform in skeletal muscle was reduced in extensor digitorum longus (EDL) muscle (81–83%) of AMPKγ1H151R transgenic mice, whereas the abundance and phosphorylation of the AMPK target acetyl-CoA carboxylase was increased in tibialis anterior muscle. Glycogen content was increased 10-fold in gastrocnemius muscle. Whole body carbohydrate oxidation was increased by 11%, and whereas glucose tolerance was unaffected, insulin sensitivity was increased in AMPKγ1H151R transgenic mice. Furthermore, perigonadal white adipose tissue mass and serum leptin were reduced in female AMPKγ1H151R transgenic mice by 38 and 51% respectively. Conversely, in male AMPKγ1H151R transgenic mice, food intake was increased (14%), but body weight and body composition were unaltered, presumably because of increased energy expenditure. In conclusion, transgenic activation of skeletal muscle AMPKγ1 in this model plays an important sex-specific role in skeletal muscle metabolism and whole body energy homeostasis.

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Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance

Journal of Experimental Medicine ◽

10.1084/jem.20201416 ◽

2020 ◽

Vol 218 (3) ◽

Author(s):

Feng He ◽

Yanrui Huang ◽

Zhi Song ◽

Huanjiao Jenny Zhou ◽

Haifeng Zhang ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Energy Homeostasis ◽

Hepatic Insulin Resistance ◽

Whole Body ◽

Ros Generation ◽

Polyubiquitin Chains ◽

Adipose Inflammation ◽

Body Energy

White adipose tissues (WAT) play crucial roles in maintaining whole-body energy homeostasis, and their dysfunction can contribute to hepatic insulin resistance and type 2 diabetes mellitus (T2DM). However, the mechanisms underlying these alterations remain unknown. By analyzing the transcriptome landscape in human adipocytes based on available RNA-seq datasets from lean, obese, and T2DM patients, we reveal elevated mitochondrial reactive oxygen species (ROS) pathway and NF-κB signaling with altered fatty acid metabolism in T2DM adipocytes. Mice with adipose-specific deletion of mitochondrial redox Trx2 develop hyperglycemia, hepatic insulin resistance, and hepatic steatosis. Trx2-deficient WAT exhibited excessive mitophagy, increased inflammation, and lipolysis. Mechanistically, mitophagy was induced through increasing ROS generation and NF-κB–dependent accumulation of autophagy receptor p62/SQSTM1, which recruits damaged mitochondria with polyubiquitin chains. Importantly, administration of ROS scavenger or NF-κB inhibitor ameliorates glucose and lipid metabolic disorders and T2DM progression in mice. Taken together, this study reveals a previously unrecognized mechanism linking mitophagy-mediated adipose inflammation to T2DM with hepatic insulin resistance.

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The two faces of reactive oxygen species (ROS) in adipocyte function and dysfunction

Biological Chemistry ◽

10.1515/hsz-2015-0305 ◽

2016 ◽

Vol 397 (8) ◽

pp. 709-724 ◽

Cited By ~ 44

Author(s):

José Pedro Castro ◽

Tilman Grune ◽

Bodo Speckmann

Keyword(s):

Oxidative Stress ◽

Reactive Oxygen Species ◽

Animal Studies ◽

Energy Homeostasis ◽

Reactive Oxygen ◽

Whole Body ◽

Oxygen Species ◽

Body Energy

Abstract White adipose tissue (WAT) is actively involved in the regulation of whole-body energy homeostasis via storage/release of lipids and adipokine secretion. Current research links WAT dysfunction to the development of metabolic syndrome (MetS) and type 2 diabetes (T2D). The expansion of WAT during oversupply of nutrients prevents ectopic fat accumulation and requires proper preadipocyte-to-adipocyte differentiation. An assumed link between excess levels of reactive oxygen species (ROS), WAT dysfunction and T2D has been discussed controversially. While oxidative stress conditions have conclusively been detected in WAT of T2D patients and related animal models, clinical trials with antioxidants failed to prevent T2D or to improve glucose homeostasis. Furthermore, animal studies yielded inconsistent results regarding the role of oxidative stress in the development of diabetes. Here, we discuss the contribution of ROS to the (patho)physiology of adipocyte function and differentiation, with particular emphasis on sources and nutritional modulators of adipocyte ROS and their functions in signaling mechanisms controlling adipogenesis and functions of mature fat cells. We propose a concept of ROS balance that is required for normal functioning of WAT. We explain how both excessive and diminished levels of ROS, e.g. resulting from over supplementation with antioxidants, contribute to WAT dysfunction and subsequently insulin resistance.

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The regulation and function of the NUAK family

Journal of Molecular Endocrinology ◽

10.1530/jme-13-0063 ◽

2013 ◽

Vol 51 (2) ◽

pp. R15-R22 ◽

Cited By ~ 31

Author(s):

Xianglan Sun ◽

Ling Gao ◽

Hung-Yu Chien ◽

Wan-Chun Li ◽

Jiajun Zhao

Keyword(s):

Protein Kinase ◽

Structural Organization ◽

Energy Homeostasis ◽

Catalytic Domain ◽

Whole Body ◽

Upstream Kinase ◽

Liver Kinase B1 ◽

And Function ◽

Amp Activated Protein Kinase ◽

Body Energy

AMP-activated protein kinase (AMPK) is a critical regulator of cellular and whole-body energy homeostasis. Twelve AMPK-related kinases (ARKs; BRSK1, BRSK2, NUAK1, NUAK2, QIK, QSK, SIK, MARK1, MARK2, MARK3, MARK4, and MELK) have been identified recently. These kinases show a similar structural organization, including an N-terminal catalytic domain, followed by a ubiquitin-associated domain and a C-terminal spacer sequence, which in some cases also contains a kinase-associated domain 1. Eleven of the ARKs are phosphorylated and activated by the master upstream kinase liver kinase B1. However, most of these ARKs are largely unknown, and the NUAK family seems to have different regulations and functions. This review contains a brief discussion of the NUAK family including the specific characteristics of NUAK1 and NUAK2.

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The Role of PDE3B Phosphorylation in the Inhibition of Lipolysis by Insulin

Molecular and Cellular Biology ◽

10.1128/mcb.00422-15 ◽

2015 ◽

Vol 35 (16) ◽

pp. 2752-2760 ◽

Cited By ~ 32

Author(s):

Lisa M. DiPilato ◽

Faiyaz Ahmad ◽

Matthew Harms ◽

Patrick Seale ◽

Vincent Manganiello ◽

...

Keyword(s):

Energy Homeostasis ◽

Phosphorylation Site ◽

Whole Body ◽

Mutant Form ◽

Brown Adipocytes ◽

Akt Phosphorylation ◽

Phosphodiesterase 3B ◽

Body Energy

Inhibition of adipocyte lipolysis by insulin is important for whole-body energy homeostasis; its disruption has been implicated as contributing to the development of insulin resistance and type 2 diabetes mellitus. The main target of the antilipolytic action of insulin is believed to be phosphodiesterase 3B (PDE3B), whose phosphorylation by Akt leads to accelerated degradation of the prolipolytic second messenger cyclic AMP (cAMP). To test this hypothesis genetically, brown adipocytes lacking PDE3B were examined for their regulation of lipolysis. InPde3bknockout (KO) adipocytes, insulin was unable to suppress β-adrenergic receptor-stimulated glycerol release. Reexpressing wild-type PDE3B in KO adipocytes fully rescued the action of insulin against lipolysis. Surprisingly, a mutant form of PDE3B that ablates the major Akt phosphorylation site, murine S273, also restored the ability of insulin to suppress lipolysis. Taken together, these data suggest that phosphorylation of PDE3B by Akt is not required for insulin to suppress adipocyte lipolysis.

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The Role of AMPK Signaling in Brown Adipose Tissue Activation

Cells ◽

10.3390/cells10051122 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1122

Author(s):

Jamie I. van der van der Vaart ◽

Mariëtte R. Boon ◽

Riekelt H. Houtkooper

Keyword(s):

Adipose Tissue ◽

Brown Adipose Tissue ◽

Whole Body ◽

Ampk Signaling ◽

Mitochondrial Homeostasis ◽

Brown Adipose ◽

Metabolic Stresses ◽

Amp Activated Protein Kinase ◽

Body Energy

Obesity is becoming a pandemic, and its prevalence is still increasing. Considering that obesity increases the risk of developing cardiometabolic diseases, research efforts are focusing on new ways to combat obesity. Brown adipose tissue (BAT) has emerged as a possible target to achieve this for its functional role in energy expenditure by means of increasing thermogenesis. An important metabolic sensor and regulator of whole-body energy balance is AMP-activated protein kinase (AMPK), and its role in energy metabolism is evident. This review highlights the mechanisms of BAT activation and investigates how AMPK can be used as a target for BAT activation. We review compounds and other factors that are able to activate AMPK and further discuss the therapeutic use of AMPK in BAT activation. Extensive research shows that AMPK can be activated by a number of different kinases, such as LKB1, CaMKK, but also small molecules, hormones, and metabolic stresses. AMPK is able to activate BAT by inducing adipogenesis, maintaining mitochondrial homeostasis and inducing browning in white adipose tissue. We conclude that, despite encouraging results, many uncertainties should be clarified before AMPK can be posed as a target for anti-obesity treatment via BAT activation.

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Energy Metabolism of Bone

Toxicologic Pathology ◽

10.1177/0192623317737065 ◽

2017 ◽

Vol 45 (7) ◽

pp. 887-893 ◽

Cited By ~ 10

Author(s):

Katherine J. Motyl ◽

Anyonya R. Guntur ◽

Adriana Lelis Carvalho ◽

Clifford J. Rosen

Keyword(s):

Bone Remodeling ◽

Energy Homeostasis ◽

Bone Structure ◽

Bone Cells ◽

Bone Cell ◽

Whole Body ◽

Blood Calcium ◽

Micro Cracks ◽

Intimate Link ◽

Body Energy

Biological processes utilize energy and therefore must be prioritized based on fuel availability. Bone is no exception to this, and the benefit of remodeling when necessary outweighs the energy costs. Bone remodeling is important for maintaining blood calcium homeostasis, repairing micro cracks and fractures, and modifying bone structure so that it is better suited to withstand loading demands. Osteoclasts, osteoblasts, and osteocytes are the primary cells responsible for bone remodeling, although bone marrow adipocytes and other cells may also play an indirect role. There is a renewed interest in bone cell energetics because of the potential for these processes to be targeted for osteoporosis therapies. In contrast, due to the intimate link between bone and energy homeostasis, pharmaceuticals that treat metabolic disease or have metabolic side effects often have deleterious bone consequences. In this brief review, we will introduce osteoporosis, discuss how bone cells utilize energy to function, evidence for bone regulating whole body energy homeostasis, and some of the unanswered questions and opportunities for further research in the field.

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AMPK as a mediator of hormonal signalling

Journal of Molecular Endocrinology ◽

10.1677/jme-09-0063 ◽

2009 ◽

Vol 44 (2) ◽

pp. 87-97 ◽

Cited By ~ 191

Author(s):

Chung Thong Lim ◽

Blerina Kola ◽

Márta Korbonits

Keyword(s):

Protein Synthesis ◽

Fatty Acid ◽

Metabolic Disorders ◽

Energy Homeostasis ◽

Metabolic Effects ◽

Whole Body ◽

Acid Oxidation ◽

Treatment Of Obesity ◽

Amp Activated Protein Kinase ◽

Hormonal Signalling

AMP-activated protein kinase (AMPK) is a key molecular player in energy homeostasis at both cellular and whole-body levels. AMPK has been shown to mediate the metabolic effects of hormones such as leptin, ghrelin, adiponectin, glucocorticoids and insulin as well as cannabinoids. Generally, activated AMPK stimulates catabolic pathways (glycolysis, fatty acid oxidation and mitochondrial biogenesis) and inhibits anabolic pathways (gluconeogenesis, glycogen, fatty acid and protein synthesis), and has a direct appetite-regulating effect in the hypothalamus. Drugs that activate AMPK, namely metformin and thiazolidinediones, are often used to treat metabolic disorders. Thus, AMPK is now recognised as a potential target for the treatment of obesity and associated co-morbidities.

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