Person: Goodyear, Laurie
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Goodyear
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Laurie
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Goodyear, Laurie
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Publication Ampk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy(Nature Publishing Group UK, 2017) Laker, Rhianna C.; Drake, Joshua C.; Wilson, Rebecca J.; Lira, Vitor A.; Lewellen, Bevan M.; Ryall, Karen A.; Fisher, Carleigh C.; Zhang, Mei; Saucerman, Jeffrey J.; Goodyear, Laurie; Kundu, Mondira; Yan, ZhenMitochondrial health is critical for skeletal muscle function and is improved by exercise training through both mitochondrial biogenesis and removal of damaged/dysfunctional mitochondria via mitophagy. The mechanisms underlying exercise-induced mitophagy have not been fully elucidated. Here, we show that acute treadmill running in mice causes mitochondrial oxidative stress at 3–12 h and mitophagy at 6 h post-exercise in skeletal muscle. These changes were monitored using a novel fluorescent reporter gene, pMitoTimer, that allows assessment of mitochondrial oxidative stress and mitophagy in vivo, and were preceded by increased phosphorylation of AMP activated protein kinase (Ampk) at tyrosine 172 and of unc-51 like autophagy activating kinase 1 (Ulk1) at serine 555. Using mice expressing dominant negative and constitutively active Ampk in skeletal muscle, we demonstrate that Ulk1 activation is dependent on Ampk. Furthermore, exercise-induced metabolic adaptation requires Ulk1. These findings provide direct evidence of exercise-induced mitophagy and demonstrate the importance of Ampk-Ulk1 signaling in skeletal muscle.Publication Decreased insulin‐stimulated brown adipose tissue glucose uptake after short‐term exercise training in healthy middle‐aged men(Blackwell Publishing Ltd, 2017) Motiani, Piryanka; Virtanen, Kirsi A.; Motiani, Kumail K.; Eskelinen, Joonas J.; Middelbeek, Roeland; Goodyear, Laurie; Savolainen, Anna M.; Kemppainen, Jukka; Jensen, Jørgen; Din, Mueez U.; Saunavaara, Virva; Parkkola, Riitta; Löyttyniemi, Eliisa; Knuuti, Juhani; Nuutila, Pirjo; Kalliokoski, Kari K.; Hannukainen, Jarna C.Aims To test the hypothesis that high‐intensity interval training (HIIT) and moderate‐intensity continuous training (MICT) improve brown adipose tissue (BAT) insulin sensitivity. Participants and methods Healthy middle‐aged men (n = 18, age 47 years [95% confidence interval {CI} 49, 43], body mass index 25.3 kg/m2 [95% CI 24.1‐26.3], peak oxygen uptake (VO2peak) 34.8 mL/kg/min [95% CI 32.1, 37.4] ) were recruited and randomized into six HIIT or MICT sessions within 2 weeks. Insulin‐stimulated glucose uptake was measured using 2‐[18F]flouro‐2‐deoxy‐D‐glucose positron‐emission tomography in BAT, skeletal muscle, and abdominal and femoral subcutaneous and visceral white adipose tissue (WAT) depots before and after the training interventions. Results: Training improved VO2peak (P = .0005), insulin‐stimulated glucose uptake into the quadriceps femoris muscle (P = .0009) and femoral subcutaneous WAT (P = .02) but not into BAT, with no difference between the training modes. Using pre‐intervention BAT glucose uptake, we next stratified subjects into high BAT (>2.9 µmol/100 g/min; n = 6) or low BAT (<2.9 µmol/100 g/min; n = 12) groups. Interestingly, training decreased insulin‐stimulated BAT glucose uptake in the high BAT group (4.0 [2.8, 5.5] vs 2.5 [1.7, 3.6]; training*BAT, P = .02), whereas there was no effect of training in the low BAT group (1.5 [1.2, 1.9] vs 1.6 [1.2, 2.0] µmol/100 g/min). Participants in the high BAT group had lower levels of inflammatory markers compared with those in the low BAT group. Conclusions: Participants with functionally active BAT have an improved metabolic profile compared with those with low BAT activity. Short‐term exercise training decreased insulin‐stimulated BAT glucose uptake in participants with active BAT, suggesting that training does not work as a potent stimulus for BAT activation.Publication Tribbles 3 Mediates Endoplasmic Reticulum Stress-Induced Insulin Resistance in Skeletal Muscle(2013) Koh, Ho-Jin; Toyoda, Taro; Didesch, Michelle M.; Lee, Min-Young; Sleeman, Mark W.; Kulkarni, Rohit; Musi, Nicolas; Hirshman, Michael F.; Goodyear, LaurieEndoplasmic Reticulum (ER) stress has been linked to insulin resistance in multiple tissues but the role of ER stress in skeletal muscle has not been explored. ER stress has also been reported to increase tribbles 3 (TRB3) expression in multiple cell lines. Here, we report that high fat feeding in mice, and obesity and type 2 diabetes in humans significantly increases TRB3 and ER stress markers in skeletal muscle. Overexpression of TRB3 in C2C12 myotubes and mouse tibialis anterior muscles significantly impairs insulin signaling. Incubation of C2C12 cells and mouse skeletal muscle with ER stressors thapsigargin and tunicamycin increases TRB3 and impairs insulin signaling and glucose uptake, effects reversed in cells overexpressing RNAi for TRB3 and in muscles from TRB3 knockout mice. Furthermore, TRB3 knockout mice are protected from high fat diet-induced insulin resistance in skeletal muscle. These data demonstrate that TRB3 mediates ER stress-induced insulin resistance in skeletal muscle.Publication Ablation of TRIP-Br2, a novel regulator of fat lipolysis, thermogenesis and oxidative metabolism, prevents diet-induced obesity and insulin resistance(2012) Liew, Chong Wee; Boucher, Jeremie; Cheong, Jit Kong; Vernochet, Cecile; Koh, Ho-Jin; Mallol, Cristina; Townsend, Kristy L; Langin, Dominique; Kawamori, Dan; Hu, Jiang; Tseng, Yu-Hua; Hellerstein, Marc K; Farmer, Stephen R; Goodyear, Laurie; Doria, Alessandro; Blüher, Matthias; Hsu, Stephen I-Hong; Kulkarni, RohitSUMMARY Obesity develops due to altered energy homeostasis favoring fat storage. Here we describe a novel transcription co-regulator for adiposity and energy metabolism, TRIP-Br2 (also called SERTAD2). TRIP-Br2 null mice are resistant to obesity and obesity-related insulin resistance. Adipocytes of the knockout (KO) mice exhibited greater stimulated lipolysis secondary to enhanced expression of hormone sensitive lipase (HSL) and β3-adrenergic (Adrb3) receptors. The KOs also exhibit higher energy expenditure due to increased adipocyte thermogenesis and oxidative metabolism by up-regulating key enzymes in respective processes. Our data show for the first time that a cell cycle transcriptional co-regulator, TRIP-Br2, modulates fat storage through simultaneous regulation of lipolysis, thermogenesis and oxidative metabolism. These data together with the observation that TRIP-BR2 expression is selectively elevated in visceral fat in obese humans suggests that this transcriptional co-regulator is a novel therapeutic target for counteracting the development of obesity, insulin resistance and hyperlipidemia.Publication Exercise Alleviates Lipid-Induced Insulin Resistance in Human Skeletal Muscle–Signaling Interaction at the Level of TBC1 Domain Family Member 4(American Diabetes Association, 2012) Pehmøller, Christian; Brandt, Nina; Birk, Jesper B.; Høeg, Louise D.; Sjøberg, Kim A.; Goodyear, Laurie; Kiens, Bente; Richter, Erik A.; Wojtaszewski, Jørgen F.P.Excess lipid availability causes insulin resistance. We examined the effect of acute exercise on lipid-induced insulin resistance and TBC1 domain family member 1/4 (TBCD1/4)-related signaling in skeletal muscle. In eight healthy young male subjects, 1 h of one-legged knee-extensor exercise was followed by 7 h of saline or intralipid infusion. During the last 2 h, a hyperinsulinemic-euglycemic clamp was performed. Femoral catheterization and analysis of biopsy specimens enabled measurements of leg substrate balance and muscle signaling. Each subject underwent two experimental trials, differing only by saline or intralipid infusion. Glucose infusion rate and leg glucose uptake was decreased by intralipid. Insulin-stimulated glucose uptake was higher in the prior exercised leg in the saline and the lipid trials. In the lipid trial, prior exercise normalized insulin-stimulated glucose uptake to the level observed in the resting control leg in the saline trial. Insulin increased phosphorylation of TBC1D1/4. Whereas prior exercise enhanced TBC1D4 phosphorylation on all investigated sites compared with the rested leg, intralipid impaired TBC1D4 S341 phosphorylation compared with the control trial. Intralipid enhanced pyruvate dehydrogenase (PDH) phosphorylation and lactate release. Prior exercise led to higher PDH phosphorylation and activation of glycogen synthase compared with resting control. In conclusion, lipid-induced insulin resistance in skeletal muscle was associated with impaired TBC1D4 S341 and elevated PDH phosphorylation. The prophylactic effect of exercise on lipid-induced insulin resistance may involve augmented TBC1D4 signaling and glycogen synthase activation.Publication Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance(Springer Berlin Heidelberg, 2016) Schulz, Tim J.; Graja, Antonia; Huang, Tian Lian; Xue, Ruidan; An, Ding; Poehle-Kronawitter, Sophie; Lynes, Matthew; Tolkachov, Alexander; O’Sullivan, Lindsay E.; Hirshman, Michael F.; Schupp, Michael; Goodyear, Laurie; Mishina, Yuji; Tseng, Yu-HuaAims/hypothesis Adipose tissue dysfunction is a prime risk factor for the development of metabolic disease. Bone morphogenetic proteins (BMPs) have previously been implicated in adipocyte formation. Here, we investigate the role of BMP signalling in adipose tissue health and systemic glucose homeostasis. Methods: We employed the Cre/loxP system to generate mouse models with conditional ablation of BMP receptor 1A in differentiating and mature adipocytes, as well as tissue-resident myeloid cells. Metabolic variables were assessed by glucose and insulin tolerance testing, insulin-stimulated glucose uptake and gene expression analysis. Results: Conditional deletion of Bmpr1a using the aP2 (also known as Fabp4)-Cre strain resulted in a complex phenotype. Knockout mice were clearly resistant to age-related impairment of insulin sensitivity during normal and high-fat-diet feeding and showed significantly improved insulin-stimulated glucose uptake in brown adipose tissue and skeletal muscle. Moreover, knockouts displayed significant reduction of variables of adipose tissue inflammation. Deletion of Bmpr1a in myeloid cells had no impact on insulin sensitivity, while ablation of Bmpr1a in mature adipocytes partially recapitulated the initial phenotype from aP2-Cre driven deletion. Co-cultivation of macrophages with pre-adipocytes lacking Bmpr1a markedly reduced expression of proinflammatory genes. Conclusions/interpretation Our findings show that altered BMP signalling in adipose tissue affects the tissue’s metabolic properties and systemic insulin resistance by altering the pattern of immune cell infiltration. The phenotype is due to ablation of Bmpr1a specifically in pre-adipocytes and maturing adipocytes rather than an immune cell-autonomous effect. Mechanistically, we provide evidence for a BMP-mediated direct crosstalk between pre-adipocytes and macrophages. Electronic supplementary material The online version of this article (doi:10.1007/s00125-016-3990-8) contains peer-reviewed but unedited supplementary material, which is available to authorised users.Publication Contraction and AICAR Stimulate IL-6 Vesicle Depletion From Skeletal Muscle Fibers In Vivo(American Diabetes Association, 2013) Lauritzen, Hans P.M.M.; Brandauer, Josef; Schjerling, Peter; Koh, Ho-Jin; Treebak, Jonas T.; Hirshman, Michael F.; Galbo, Henrik; Goodyear, LaurieRecent studies suggest that interleukin 6 (IL-6) is released from contracting skeletal muscles; however, the cellular origin, secretion kinetics, and signaling mechanisms regulating IL-6 secretion are unknown. To address these questions, we developed imaging methodology to study IL-6 in fixed mouse muscle fibers and in live animals in vivo. Using confocal imaging to visualize endogenous IL-6 protein in fixed muscle fibers, we found IL-6 in small vesicle structures distributed throughout the fibers under basal (resting) conditions. To determine the kinetics of IL-6 secretion, intact quadriceps muscles were transfected with enhanced green fluorescent protein (EGFP)-tagged IL-6 (IL-6-EGFP), and 5 days later anesthetized mice were imaged before and after muscle contractions in situ. Contractions decreased IL-6-EGFP–containing vesicles and protein by 62% (P < 0.05), occurring rapidly and progressively over 25 min of contraction. However, contraction-mediated IL-6-EGFP reduction was normal in muscle-specific AMP-activated protein kinase (AMPK) α2-inactive transgenic mice. In contrast, the AMPK activator AICAR decreased IL-6-EGFP vesicles, an effect that was inhibited in the transgenic mice. In conclusion, resting skeletal muscles contain IL-6–positive vesicles that are expressed throughout myofibers. Contractions stimulate the rapid reduction of IL-6 in myofibers, occurring through an AMPKα2-independent mechanism. This novel imaging methodology clearly establishes IL-6 as a contraction-stimulated myokine and can be used to characterize the secretion kinetics of other putative myokines.Publication Clonal analyses and gene profiling identify genetic biomarkers of human brown and white preadipocyte thermogenic potential(2015) Xue, Ruidan; Lynes, Matthew; Dreyfuss, Jonathan M.; Shamsi, Farnaz; Schulz, Tim J.; Zhang, Hongbin; Huang, Tian Lian; Townsend, Kristy L.; Li, Yiming; Takahashi, Hirokazu; Weiner, Lauren S.; White, Andrew; Lynes, Maureen S.; Rubin, Lee; Goodyear, Laurie; Cypess, Aaron M.; Tseng, Yu-HuaTargeting brown adipose tissue (BAT) content or activity has therapeutic potential for treating obesity and the metabolic syndrome by increasing energy expenditure. Both inter- and intra-individual differences contribute to heterogeneity in human BAT and potentially to differential thermogenic capacity in human populations. Here, we demonstrated the generated clones of brown and white preadipocytes from human neck fat of four individuals and characterized their adipogenic differentiation and thermogenic function. Combining an uncoupling protein 1(UCP1) reporter system and expression profiling, we defined novel sets of gene signatures in human preadipocytes that could predict the thermogenic potential of the cells once they were maturated in culture. Knocking out the positive UCP1 regulators identified by this approach, PREX1 and EDNRB in brown preadipocytes using CRISPR/Cas9 markedly abolished the high level of UCP1 in brown adipocytes differentiated from the preadipocytes. Finally, we were able to prospectively isolate adipose progenitors with great thermogenic potential using cell surface marker CD29. These data provide new insights into the cellular heterogeneity in human fat and offer the identification of possible biomarkers of thermogenically competent preadipocytes.Publication Contraction stimulates muscle glucose uptake independent of atypical PKC(John Wiley & Sons, Ltd, 2015) Yu, Haiyan; Fujii, Nobuharu L; Toyoda, Taro; An, Ding; Farese, Robert V; Leitges, Michael; Hirshman, Michael F; Mul, Joram D.; Goodyear, LaurieExercise increases skeletal muscle glucose uptake, but the underlying mechanisms are only partially understood. The atypical protein kinase C (PKC) isoforms λ and ζ (PKC-λ/ζ) have been shown to be necessary for insulin-, AICAR-, and metformin-stimulated glucose uptake in skeletal muscle, but not for treadmill exercise-stimulated muscle glucose uptake. To investigate if PKC-λ/ζ activity is required for contraction-stimulated muscle glucose uptake, we used mice with tibialis anterior muscle-specific overexpression of an empty vector (WT), wild-type PKC-ζ (PKC-ζWT), or an enzymatically inactive T410A-PKC-ζ mutant (PKC-ζT410A). We also studied skeletal muscle-specific PKC-λ knockout (MλKO) mice. Basal glucose uptake was similar between WT, PKC-ζWT, and PKC-ζT410A tibialis anterior muscles. In contrast, in situ contraction-stimulated glucose uptake was increased in PKC-ζT410A tibialis anterior muscles compared to WT or PKC-ζWT tibialis anterior muscles. Furthermore, in vitro contraction-stimulated glucose uptake was greater in soleus muscles of MλKO mice than WT controls. Thus, loss of PKC-λ/ζ activity increases contraction-stimulated muscle glucose uptake. These data clearly demonstrate that PKC-λ ζ activity is not necessary for contraction-stimulated glucose uptake.Publication The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue(Springer Nature, 2017) Lynes, Matthew; Leiria, Luiz; Lundh, Morten; Bartelt, Alexander; Shamsi, Farnaz; Huang, Tianwen; Takahashi, Hirokazu; Hirshman, Michael F; Schlein, Christian; Lee, Alexandra; Baer, Lisa A; May, Francis J; Gao, Fei; Narain, Niven R; Chen, Emily Y; Kiebish, Michael A; Cypess, Aaron; Blüher, Matthias; Goodyear, Laurie; Hotamisligil, Gokhan; Stanford, Kristin I; Tseng, Yu-HuaBrown adipose tissue (BAT) and beige adipose tissue combust fuels for heat production in adult humans, and so constitute an appealing target for the treatment of metabolic disorders such as obesity, diabetes and hyperlipidemia1,2. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism3–5. These therapies, however, are time consuming and uncomfortable, demonstrating the need for pharmacological interventions. Recently, lipids have been identified that are released from tissues and act locally or systemically to promote insulin sensitivity and glucose tolerance; as a class, these lipids are referred to as ‘lipokines’6–8. Because BAT is a specialized metabolic tissue that takes up and burns lipids and is linked to systemic metabolic homeostasis, we hypothesized that there might be thermogenic lipokines that activate BAT in response to cold. Here we show that the lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) is a stimulator of BAT activity, and that its levels are negatively correlated with body-mass index and insulin sensitivity. Using a global lipidomic analysis, we found that 12,13-diHOME was increased in the circulation of humans and mice exposed to cold. Furthermore, we found that the enzymes that produce 12,13-diHOME were uniquely induced in BAT by cold stimulation. The injection of 12,13-diHOME acutely activated BAT fuel uptake and enhanced cold tolerance, which resulted in decreased levels of serum triglycerides. Mechanistically, 12,13-diHOME increased fatty acid (FA) uptake into brown adipocytes by promoting the translocation of the FA transporters FATP1 and CD36 to the cell membrane. These data suggest that 12,13-diHOME, or a functional analog, could be developed as a treatment for metabolic disorders.