Publications by authors named "Michael F Hirshman"

89 Publications

The MicroRNA miR-696 is Regulated by SNARK and Reduces Mitochondrial Activity in Mouse Skeletal Muscle Through Pgc1α Inhibition.

Mol Metab 2021 Mar 31:101226. Epub 2021 Mar 31.

Obesity and Comorbidities Research Center, OCRC, IB, UNICAMP, Campinas, Brazil. Electronic address:

MicroRNAs (miRNA) are known to regulate expression of genes involved in several physiological processes including metabolism, mitochondrial biogenesis, proliferation, differentiation, and cell death. Using "in silico" analyses, we identified 219 unique miRNAs that potentially bind to the 3'UTR region of a critical mitochondrial regulator, the peroxisome proliferator-activated receptor gamma coactivator (PGC) 1 alpha (Pgc1α). Out of the 219 candidate miRNAs, miR-696 had one of the highest interactions at the 3'UTR of Pgc1α, suggesting that miR-696 may be involved in the regulation of Pgc1α. Consistent with this hypothesis, we found that miR-696 was highly expressed in the skeletal muscle of both STZ-induced diabetic mice and chronic high-fat fed mice. C2C12 muscle cells exposed to palmitic acid also exhibited higher expression of miR-696. This increased expression corresponded with reduced expression of oxidative metabolism genes and reduced mitochondrial respiration. Importantly, reduction of miR-696 reversed decreases in mitochondrial activity in response to palmitic acid. Using C2C12 cells treated with the AMP-activated protein kinase (AMPK) activator AICAR and skeletal muscle from AMPKα2 dominant negative (DN) mice, we found that the signaling mechanism regulating miR-696 does not involve AMPK. In contrast, overexpression of SNF1-AMPK-related kinase (SNARK) in C2C12 cells increased miR-696 transcription while the knockdown of SNARK significantly decreased miR-696. Moreover, muscle-specific transgenic mice overexpressing SNARK exhibited lower expression of Pgc1α, elevated levels of miR-696, and reduced amounts of spontaneous activity. Our findings demonstrate that metabolic stress increases miR-696 expression in skeletal muscle cells, which in turn inhibits Pgc1α, reducing mitochondrial function. SNARK plays a role in this process as a metabolic stress signaling molecule inducing the expression of miR-696.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2021.101226DOI Listing
March 2021

Placental superoxide dismutase 3 mediates benefits of maternal exercise on offspring health.

Cell Metab 2021 Mar 19. Epub 2021 Mar 19.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA. Electronic address:

Poor maternal diet increases the risk of obesity and type 2 diabetes in offspring, adding to the ever-increasing prevalence of these diseases. In contrast, we find that maternal exercise improves the metabolic health of offspring, and here, we demonstrate that this occurs through a vitamin D receptor-mediated increase in placental superoxide dismutase 3 (SOD3) expression and secretion. SOD3 activates an AMPK/TET signaling axis in fetal offspring liver, resulting in DNA demethylation at the promoters of glucose metabolic genes, enhancing liver function, and improving glucose tolerance. In humans, SOD3 is upregulated in serum and placenta from physically active pregnant women. The discovery of maternal exercise-induced cross talk between placenta-derived SOD3 and offspring liver provides a central mechanism for improved offspring metabolic health. These findings may lead to novel therapeutic approaches to limit the transmission of metabolic disease to the next generation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2021.03.004DOI Listing
March 2021

Exercise Training Promotes Sex-Specific Adaptations in Mouse Inguinal White Adipose Tissue.

Diabetes 2021 Feb 9. Epub 2021 Feb 9.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA

Recent studies demonstrate that adaptations to white adipose tissue are important components of the beneficial effects of exercise training on metabolic health. Exercise training favorably alters the phenotype of subcutaneous inguinal white adipose tissue (iWAT) in male mice including decreasing fat mass, improving mitochondrial function, inducing beiging and stimulating the secretion of adipokines. Here, we find that despite performing more voluntary wheel running compared to males, these adaptations do not occur in the iWAT of female mice. Consistent with sex-specific adaptations, we report that mRNA expression of androgen receptor co-activators are upregulated in iWAT from trained male mice, and that testosterone treatment of primary adipocytes derived from the iWAT of male, but not female mice, phenocopies exercise-induced metabolic adaptations. Sex-specificity also occurs in the secretome profile, as we identify Cysteine Rich Secretory Protein 1() as a novel adipokine that is only secreted from male iWAT in response to exercise. expression is upregulated by testosterone and functions to increase glucose and fatty acid uptake. Our finding that adaptations to iWAT with exercise training are dramatically greater in male mice has potential clinical implications for understanding the different metabolic response to exercise training in males and females, and demonstrates the importance of investigating both sexes in studies of adipose tissue biology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db20-0790DOI Listing
February 2021

Exercise training reverses cancer-induced oxidative stress and decrease in muscle COPS2/TRIP15/ALIEN.

Mol Metab 2020 09 11;39:101012. Epub 2020 May 11.

School of Physical Education and Sport, University of Sao Paulo, Sao Paulo, Brazil. Electronic address:

Objective: We tested the hypothesis that exercise training would attenuate metabolic impairment in a model of severe cancer cachexia.

Methods: We used multiple in vivo and in vitro methods to explore the mechanisms underlying the beneficial effects induced by exercise training in tumor-bearing rats.

Results: Exercise training improved running capacity, prolonged lifespan, reduced oxidative stress, and normalized muscle mass and contractile function in tumor-bearing rats. An unbiased proteomic screening revealed COP9 signalosome complex subunit 2 (COPS2) as one of the most downregulated proteins in skeletal muscle at the early stage of cancer cachexia. Exercise training normalized muscle COPS2 protein expression in tumor-bearing rats and mice. Lung cancer patients with low endurance capacity had low muscle COPS2 protein expression as compared to age-matched control subjects. To test whether decrease in COPS2 protein levels could aggravate or be an intrinsic compensatory mechanism to protect myotubes from cancer effects, we performed experiments in vitro using primary myotubes. COPS2 knockdown in human myotubes affected multiple cellular pathways, including regulation of actin cytoskeleton. Incubation of cancer-conditioned media in mouse myotubes decreased F-actin expression, which was partially restored by COPS2 knockdown. Direct repeat 4 (DR4) response elements have been shown to positively regulate gene expression. COPS2 overexpression decreased the DR4 activity in mouse myoblasts, and COPS2 knockdown inhibited the effects of cancer-conditioned media on DR4 activity.

Conclusions: These studies demonstrated that exercise training may be an important adjuvant therapy to counteract cancer cachexia and uncovered novel mechanisms involving COPS2 to regulate myotube homeostasis in cancer cachexia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2020.101012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283151PMC
September 2020

Maternal and paternal exercise regulate offspring metabolic health and beta cell phenotype.

BMJ Open Diabetes Res Care 2020 02;8(1)

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, Massachusetts, USA

Objective: Poor maternal and paternal environments increase the risk for obesity and diabetes in offspring, whereas maternal and paternal exercise in mice can improve offspring metabolic health. We determined the effects of combined maternal and paternal exercise on offspring health and the effects of parental exercise on offspring pancreas phenotype, a major tissue regulating glucose homeostasis.

Research Design And Methods: Breeders were high fat fed and housed±running wheels before breeding (males) and before and during gestation (females). Offspring groups were: both parents sedentary (Sed); maternal exercise only (Mat Ex); paternal exercise only (Pat Ex); and maternal+paternal exercise (Mat+Pat Ex). Offspring were sedentary, chow fed, and studied at weaning, 12, 20 and 52 weeks.

Results: While there was no effect of parental exercise on glucose tolerance at younger ages, at 52 weeks, offspring of Mat Ex, Pat Ex and Mat+Pat Ex displayed lower glycemia and improved glucose tolerance. The greatest effects were in offspring from parents that both exercised (Mat+Pat Ex). Offspring from Mat Ex, Pat Ex, and Mat+Pat Ex had decreased beta cell size, whereas islet size and beta cell mass only decreased in Mat+Pat Ex offspring.

Conclusions: Maternal and paternal exercise have additive effects to improve glucose tolerance in offspring as they age, accompanied by changes in the offspring endocrine pancreas. These findings have important implications for the prevention and treatment of type 2 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjdrc-2019-000890DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7050345PMC
February 2020

Loss of FoxOs in muscle reveals sex-based differences in insulin sensitivity but mitigates diet-induced obesity.

Mol Metab 2019 12 10;30:203-220. Epub 2019 Oct 10.

Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA. Electronic address:

Objective: Gender influences obesity-related complications, including diabetes. Females are more protected from insulin resistance after diet-induced obesity, which may be related to fat accumulation and muscle insulin sensitivity. FoxOs regulate muscle atrophy and are targets of insulin action, but their role in muscle insulin sensitivity and mitochondrial metabolism is unknown.

Methods: We measured muscle insulin signaling, mitochondrial energetics, and metabolic responses to a high-fat diet (HFD) in male and female muscle-specific FoxO1/3/4 triple knock-out (TKO) mice.

Results: In male TKO muscle, insulin-stimulated AKT activation was decreased. AKT2 protein and mRNA levels were reduced and insulin receptor protein and IRS-2 mRNA decreased. These changes contributed to decreased insulin-stimulated glucose uptake in glycolytic muscle in males. In contrast, female TKOs maintain normal insulin-mediated AKT phosphorylation, normal AKT2 levels, and normal glucose uptake in glycolytic muscle. When challenged with a HFD, fat gain was attenuated in both male and female TKO mice, and associated with decreased glucose levels, improved glucose homeostasis, and reduced muscle triglyceride accumulation. Furthermore, female TKO mice showed increased energy expenditure, relative to controls, due to increased lean mass and maintenance of mitochondrial function in muscle.

Conclusions: FoxO deletion in muscle uncovers sexually dimorphic regulation of AKT2, which impairs insulin signaling in male mice, but not females. However, loss of FoxOs in muscle from both males and females also leads to muscle hypertrophy and increases in metabolic rate. These factors mitigate fat gain and attenuate metabolic abnormalities in response to a HFD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molmet.2019.10.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819874PMC
December 2019

Reduced sucrose nonfermenting AMPK-related kinase (SNARK) activity aggravates cancer-induced skeletal muscle wasting.

Biomed Pharmacother 2019 Sep 6;117:109197. Epub 2019 Jul 6.

Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address:

Sucrose nonfermenting AMPK-related kinase (SNARK) is a member of the AMPK family of kinases and has been implicated in the regulation of critical metabolic processes. Recent findings demonstrate that SNARK has an important role in the maintenance of muscle mass with age. Loss of skeletal muscle mass (cachexia) is a key problem for cancer patients. Thus, based on our previous findings with aging, we hypothesized that SNARK would play a role in regulating muscle mass under conditions of cancer cachexia. To test this hypothesis, Lewis Lung Carcinoma tumor cells or vehicle were injected subcutaneously in the right flank of wild type mice, muscle-specific transgenic mice expressing inactive SNARK mutant (SDN) or muscle-specific transgenic mice overexpressing wild-type SNARK (SWT). All tumor-bearing mice presented muscle wasting compared to vehicle-injected mice. However, SDN tumor-bearing mice had more pronounced atrophy compared to wild-type and SWT tumor-bearing mice. Histological analysis confirmed muscle atrophy in tumor-bearing mice, and SDN tumor-bearing mice exhibited a significantly smaller skeletal muscle cross-sectional area than wild-type and SWT tumor-bearing mice. Moreover, SDN tumor-bearing mice had increased skeletal muscle BAX protein expression, a marker of apoptosis, compared to other groups.Thus, lack of SNARK in skeletal muscle aggravates cancer-induced skeletal muscle wasting. These findings uncover a role for SNARK in the maintenance of skeletal muscle mass under cachexia conditions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopha.2019.109197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6686878PMC
September 2019

Role of p110a subunit of PI3-kinase in skeletal muscle mitochondrial homeostasis and metabolism.

Nat Commun 2019 07 30;10(1):3412. Epub 2019 Jul 30.

Section of Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA.

Skeletal muscle insulin resistance, decreased phosphatidylinositol 3-kinase (PI3K) activation and altered mitochondrial function are hallmarks of type 2 diabetes. To determine the relationship between these abnormalities, we created mice with muscle-specific knockout of the p110α or p110β catalytic subunits of PI3K. We find that mice with muscle-specific knockout of p110α, but not p110β, display impaired insulin signaling and reduced muscle size due to enhanced proteasomal and autophagic activity. Despite insulin resistance and muscle atrophy, M-p110αKO mice show decreased serum myostatin, increased mitochondrial mass, increased mitochondrial fusion, and increased PGC1α expression, especially PCG1α2 and PCG1α3. This leads to enhanced mitochondrial oxidative capacity, increased muscle NADH content, and higher muscle free radical release measured in vivo using pMitoTimer reporter. Thus, p110α is the dominant catalytic isoform of PI3K in muscle in control of insulin sensitivity and muscle mass, and has a unique role in mitochondrial homeostasis in skeletal muscle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11265-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6667496PMC
July 2019

12-Lipoxygenase Regulates Cold Adaptation and Glucose Metabolism by Producing the Omega-3 Lipid 12-HEPE from Brown Fat.

Cell Metab 2019 10 25;30(4):768-783.e7. Epub 2019 Jul 25.

Joslin Diabetes Center, Section on Integrative Physiology and Metabolism, Harvard Medical School, Boston, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA. Electronic address:

Distinct oxygenases and their oxylipin products have been shown to participate in thermogenesis by mediating physiological adaptations required to sustain body temperature. Since the role of the lipoxygenase (LOX) family in cold adaptation remains elusive, we aimed to investigate whether, and how, LOX activity is required for cold adaptation and to identify LOX-derived lipid mediators that could serve as putative cold mimetics with therapeutic potential to combat diabetes. By utilizing mass-spectrometry-based lipidomics in mice and humans, we demonstrated that cold and β3-adrenergic stimulation could promote the biosynthesis and release of 12-LOX metabolites from brown adipose tissue (BAT). Moreover, 12-LOX ablation in mouse brown adipocytes impaired glucose uptake and metabolism, resulting in blunted adaptation to the cold in vivo. The cold-induced 12-LOX product 12-HEPE was found to be a batokine that improves glucose metabolism by promoting glucose uptake into adipocytes and skeletal muscle through activation of an insulin-like intracellular signaling pathway.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2019.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774888PMC
October 2019

TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism.

Nat Metab 2019 02 11;1(2):291-303. Epub 2019 Feb 11.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

Exercise improves health and well-being across diverse organ systems, and elucidating mechanisms underlying the beneficial effects of exercise can lead to new therapies. Here, we show that transforming growth factor-β2 (TGF-β2) is secreted from adipose tissue in response to exercise and improves glucose tolerance in mice. We identify TGF-β2 as an exercise-induced adipokine in a gene expression analysis of human subcutaneous adipose tissue biopsies after exercise training. In mice, exercise training increases TGF-β2 in scWAT, serum, and its secretion from fat explants. Transplanting scWAT from exercise-trained wild type mice, but not from adipose tissue-specific Tgfb2-/- mice, into sedentary mice improves glucose tolerance. TGF-β2 treatment reverses the detrimental metabolic effects of high fat feeding in mice. Lactate, a metabolite released from muscle during exercise, stimulates TGF-β2 expression in human adipocytes. Administration of the lactate-lowering agent dichloroacetate during exercise training in mice decreases circulating TGF-β2 levels and reduces exercise-stimulated improvements in glucose tolerance. Thus, exercise training improves systemic metabolism through inter-organ communication with fat via a lactate-TGF-β2-signaling cycle.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s42255-018-0030-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6481955PMC
February 2019

Paternal Exercise Improves Glucose Metabolism in Adult Offspring.

Diabetes 2018 12 21;67(12):2530-2540. Epub 2018 Oct 21.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA

Poor paternal diet has emerged as a risk factor for metabolic disease in offspring, and alterations in sperm may be a major mechanism mediating these detrimental effects of diet. Although exercise in the general population is known to improve health, the effects of paternal exercise on sperm and offspring metabolic health are largely unknown. Here, we studied 7-week-old C57BL/6 male mice fed a chow or high-fat diet and housed either in static cages (sedentary) or cages with attached running wheels (exercise trained). After 3 weeks, one cohort of males was sacrificed and cauda sperm obtained, while the other cohort was bred with chow-fed sedentary C57BL/6 females. Offspring were chow fed, sedentary, and studied during the first year of life. We found that high-fat feeding of sires impairs glucose tolerance and increases the percentage of fat mass in both male and female offspring at 52 weeks of age. Strikingly, paternal exercise suppresses the effects of paternal high-fat diet on offspring, reversing the observed impairment in glucose tolerance, percentage of fat mass, and glucose uptake in skeletal muscles of the offspring. These changes in offspring phenotype are accompanied by changes in sperm physiology, as, for example, high-fat feeding results in decreased sperm motility, an effect normalized in males subject to exercise training. Deep sequencing of sperm reveals pronounced effects of exercise training on multiple classes of small RNAs, as multiple changes to the sperm RNA payload observed in animals consuming a high-fat diet are suppressed by exercise training. Thus, voluntary exercise training of male mice results in pronounced improvements in the metabolic health of adult male and female offspring. We provide the first in-depth analysis of small RNAs in sperm from exercise-trained males, revealing a marked change in the levels of multiple small RNAs with the potential to alter phenotypes in the next generation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db18-0667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6245224PMC
December 2018

Sucrose nonfermenting AMPK-related kinase (SNARK) regulates exercise-stimulated and ischemia-stimulated glucose transport in the heart.

J Cell Biochem 2019 01 7;120(1):685-696. Epub 2018 Sep 7.

Integrative Physiology and Metabolism Section, Joslin Diabetes Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts.

The signaling mechanisms mediating myocardial glucose transport are not fully understood. Sucrose nonfermenting AMP-activated protein kinase (AMPK)-related kinase (SNARK) is an AMPK-related protein kinase that is expressed in the heart and has been implicated in contraction-stimulated glucose transport in mouse skeletal muscle. We first determined if SNARK is phosphorylated on Thr , a site critical for SNARK activity. Mice were treated with exercise, ischemia, submaximal insulin, or maximal insulin. Treadmill exercise slightly, but significantly increased SNARK Thr phosphorylation. Ischemia also increased SNARK Thr phosphorylation, but there was no effect of submaximal or maximal insulin. HL1 cardiomyocytes were used to overexpress wild-type (WT) SNARK and to knockdown endogenous SNARK. Overexpression of WT SNARK had no effect on ischemia-stimulated glucose transport; however, SNARK knockdown significantly decreased ischemia-stimulated glucose transport. SNARK overexpression or knockdown did not alter insulin-stimulated glucose transport or glycogen concentrations. To study SNARK function in vivo, SNARK heterozygous knockout mice (SNARK ) and WT littermates performed treadmill exercise. Exercise-stimulated glucose transport was decreased by ~50% in hearts from SNARK mice. In summary, exercise and ischemia increase SNARK Thr phosphorylation in the heart and SNARK regulates exercise-stimulated and ischemia-stimulated glucose transport. SNARK is a novel mediator of insulin-independent glucose transport in the heart.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.27425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6347018PMC
January 2019

JNK regulates muscle remodeling via myostatin/SMAD inhibition.

Nat Commun 2018 08 2;9(1):3030. Epub 2018 Aug 2.

Research Division, Joslin Diabetes Center, Boston, 02215, MA, USA.

Skeletal muscle has a remarkable plasticity to adapt and remodel in response to environmental cues, such as physical exercise. Endurance exercise stimulates improvements in muscle oxidative capacity, while resistance exercise induces muscle growth. Here we show that the c-Jun N-terminal kinase (JNK) is a molecular switch that when active, stimulates muscle fibers to grow, resulting in increased muscle mass. Conversely, when muscle JNK activation is suppressed, an alternative remodeling program is initiated, resulting in smaller, more oxidative muscle fibers, and enhanced aerobic fitness. When muscle is exposed to mechanical stress, JNK initiates muscle growth via phosphorylation of the transcription factor, SMAD2, at specific linker region residues leading to inhibition of the growth suppressor, myostatin. In human skeletal muscle, this JNK/SMAD signaling axis is activated by resistance exercise, but not endurance exercise. We conclude that JNK acts as a key mediator of muscle remodeling during exercise via regulation of myostatin/SMAD signaling.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-018-05439-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6072737PMC
August 2018

Voluntary wheel running promotes resilience to chronic social defeat stress in mice: a role for nucleus accumbens ΔFosB.

Neuropsychopharmacology 2018 08 24;43(9):1934-1942. Epub 2018 May 24.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, 02215, USA.

Elucidating mechanisms by which physical exercise promotes resilience, the brain's ability to cope with prolonged stress exposure while maintaining normal psychological functioning, is a major research challenge given the high prevalence of stress-related mental disorders, including major depressive disorder. Chronic voluntary wheel running (VWR), a rodent model that mimics aspects of human physical exercise, induces the transcription factor ΔFosB in the nucleus accumbens (NAc), a key reward-related brain area. ΔFosB expression in NAc modulates stress susceptibility. Here, we explored whether VWR induction of NAc ΔFosB promotes resilience to chronic social defeat stress (CSDS). Male young-adult C57BL/6J mice were single housed for up to 21 d with or without running wheels and then subjected to 10 d of CSDS. Stress-exposed sedentary mice developed a depressive-like state, characterized by anhedonia and social avoidance, whereas stress-exposed mice that had been wheel running showed resilience. Functional inhibition of NAc ΔFosB during VWR, by viral-mediated overexpression of a transcriptionally inactive JunD mutant, reinstated susceptibility to CSDS. Within the NAc, VWR induction of ΔFosB was CREB-dependent, associated with altered dendritic morphology, and medium spiny neuron (MSN) subtype specific in the NAc core and shell subregions. Finally, when mice performed VWR following the onset of CSDS-induced social avoidance, VWR normalized such behavior. These data indicate that VWR promoted resilience to CSDS, and suggest that sustained induction of ΔFosB in the NAc underlies, at least in part, the stress resilience mediated by VWR. These findings provide a potential framework for the development of treatments for stress-associated mental illnesses based on physical exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-018-0103-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6046059PMC
August 2018

12,13-diHOME: An Exercise-Induced Lipokine that Increases Skeletal Muscle Fatty Acid Uptake.

Cell Metab 2018 May;27(5):1111-1120.e3

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, One Joslin Place, Boston, MA 02215, USA. Electronic address:

Circulating factors released from tissues during exercise have been hypothesized to mediate some of the health benefits of regular physical activity. Lipokines are circulating lipid species that have recently been reported to affect metabolism in response to cold. Here, lipidomics analysis revealed that a bout of moderate-intensity exercise causes a pronounced increase in the circulating lipid 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) in male, female, young, old, sedentary, and active human subjects. In mice, both a single bout of exercise and exercise training increased circulating 12,13-diHOME and surgical removal of brown adipose tissue (BAT) negated the increase in 12,13-diHOME, suggesting that BAT is the tissue source for exercise-stimulated 12,13-diHOME. Acute 12,13-diHOME treatment of mice in vivo increased skeletal muscle fatty acid uptake and oxidation, but not glucose uptake. These data reveal that lipokines are novel exercise-stimulated circulating factors that may contribute to the metabolic changes that occur with physical exercise.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cmet.2018.03.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5935136PMC
May 2018

Tribbles 3 regulates protein turnover in mouse skeletal muscle.

Biochem Biophys Res Commun 2017 11 27;493(3):1236-1242. Epub 2017 Sep 27.

Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, SC 29208, USA. Electronic address:

Skeletal muscle atrophy is associated with a disruption in protein turnover involving increased protein degradation and suppressed protein synthesis. Although it has been well studied that the IGF-1/PI3K/Akt pathway plays an essential role in the regulation of the protein turnover, molecule(s) that triggers the change in protein turnover still remains to be elucidated. TRB3 has been shown to inhibit Akt through direct binding. In this study, we hypothesized that TRB3 in mouse skeletal muscle negatively regulates protein turnover via the disruption of Akt and its downstream molecules. Muscle-specific TRB3 transgenic (TRB3TG) mice had decreased muscle mass and fiber size, resulting in impaired muscle function. We also found that protein synthesis rate and signaling molecules, mTOR and S6K1, were significantly reduced in TRB3TG mice, whereas the protein breakdown pathway was significantly activated. In contrast, TRB3 knockout mice showed increased muscle mass and had an increase in protein synthesis rate, but decreases in FoxOs, atrogin-1, and MuRF-1. These findings indicate that TRB3 regulates protein synthesis and breakdown via the Akt/mTOR/FoxO pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbrc.2017.09.134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675010PMC
November 2017

Maternal Exercise Improves Glucose Tolerance in Female Offspring.

Diabetes 2017 08 1;66(8):2124-2136. Epub 2017 Jun 1.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA

Poor maternal diet can lead to metabolic disease in offspring, whereas maternal exercise may have beneficial effects on offspring health. In this study, we determined ifmaternal exercise could reverse the detrimental effects of maternal high-fat feeding on offspring metabolism of female mice. C57BL/6 female mice were fed a chow (21%) or high-fat (60%) diet and further divided by housing in static cages or cages with running wheels for 2 weeks prior to breeding and throughout gestation. Females were bred with chow-fed sedentary C57BL/6 males. High fat-fed sedentary dams produced female offspring with impaired glucose tolerance compared with offspring of chow-fed dams throughout their first year of life, an effect not present in the offspring from high fat-fed dams that had trained. Offspring from high fat-fed trained dams had normalized glucose tolerance, decreased fasting insulin, and decreased adiposity. Liver metabolic function, measured by hepatic glucose production in isolated hepatocytes, hyperinsulinemic-euglycemic clamps, liver triglyceride content, and liver enzyme expression, was enhanced in offspring from trained dams. In conclusion, maternal exercise negates the detrimental effects of a maternal high-fat diet on glucose tolerance and hepatocyte glucose metabolism in female offspring. The ability of maternal exercise to improve the metabolic health of female offspring is important, as this intervention could combat the transmission of obesity and diabetes to subsequent generations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db17-0098DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5521858PMC
August 2017

The cold-induced lipokine 12,13-diHOME promotes fatty acid transport into brown adipose tissue.

Nat Med 2017 May 27;23(5):631-637. Epub 2017 Mar 27.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA.

Brown 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 hyperlipidemia. Cold exposure can enhance energy expenditure by activating BAT, and it has been shown to improve nutrient metabolism. 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'. 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/nm.4297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5699924PMC
May 2017

Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis.

J Clin Invest 2016 09 15;126(9):3433-46. Epub 2016 Aug 15.

Diabetes strongly impacts protein metabolism, particularly in skeletal muscle. Insulin and IGF-1 enhance muscle protein synthesis through their receptors, but the relative roles of each in muscle proteostasis have not been fully elucidated. Using mice with muscle-specific deletion of the insulin receptor (M-IR-/- mice), the IGF-1 receptor (M-IGF1R-/- mice), or both (MIGIRKO mice), we assessed the relative contributions of IR and IGF1R signaling to muscle proteostasis. In differentiated muscle, IR expression predominated over IGF1R expression, and correspondingly, M-IR-/- mice displayed a moderate reduction in muscle mass whereas M-IGF1R-/- mice did not. However, these receptors serve complementary roles, such that double-knockout MIGIRKO mice displayed a marked reduction in muscle mass that was linked to increases in proteasomal and autophagy-lysosomal degradation, accompanied by a high-protein-turnover state. Combined muscle-specific deletion of FoxO1, FoxO3, and FoxO4 in MIGIRKO mice reversed increased autophagy and completely rescued muscle mass without changing proteasomal activity. These data indicate that signaling via IR is more important than IGF1R in controlling proteostasis in differentiated muscle. Nonetheless, the overlap of IR and IGF1R signaling is critical to the regulation of muscle protein turnover, and this regulation depends on suppression of FoxO-regulated, autophagy-mediated protein degradation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI86522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004956PMC
September 2016

Loss of BMP receptor type 1A in murine adipose tissue attenuates age-related onset of insulin resistance.

Diabetologia 2016 08 21;59(8):1769-77. Epub 2016 May 21.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, One Joslin Place, Boston, MA, 02215, USA.

Aims/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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-016-3990-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4930470PMC
August 2016

Relationship of brown adipose tissue perfusion and function: a study through β2-adrenoreceptor stimulation.

J Appl Physiol (1985) 2016 Apr 28;120(8):825-32. Epub 2016 Jan 28.

Cardiac Ultrasound Laboratory and Cardiovascular Research Center, Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;

Brown adipose tissue (BAT) activation increases glucose and lipid consumption; as such, it is been considered as a potential therapy to decrease obesity. BAT is highly vascularized and its activation is associated with a necessary increase in blood flow. However, whether increasing BAT blood flow per se increases BAT activity is unknown. To examine this hypothesis, we investigated whether an isolated increase in BAT blood flow obtained by β2-adrenoreceptor (β2-AR) stimulation with salbutamol increased BAT activity. BAT blood flow was estimated in vivo in mice using contrast-enhanced ultrasound. The absence of direct effect of salbutamol on the function of isolated brown adipocytes was assessed by measuring oxygen consumption. The effect of salbutamol on BAT activity was investigated by measuring BAT glucose uptake in vivo. BAT blood flow increased by 2.3 ± 0.6-fold during β2-AR stimulation using salbutamol infusion in mice (P= 0.003). β2-AR gene expression was detectable in BAT but was extremely low in isolated brown adipocytes. Oxygen consumption of isolated brown adipocytes did not change with salbutamol exposure, confirming the absence of a direct effect of β2-AR agonist on brown adipocytes. Finally, β2-AR stimulation by salbutamol increased BAT glucose uptake in vivo (991 ± 358 vs. 135 ± 49 ng glucose/mg tissue/45 min in salbutamol vs. saline injected mice, respectively,P= 0.046). In conclusion, an increase in BAT blood flow without direct stimulation of the brown adipocytes is associated with increased BAT metabolic activity. Increasing BAT blood flow might represent a new therapeutic target in obesity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/japplphysiol.00634.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835910PMC
April 2016

The AMPK-related kinase SNARK regulates muscle mass and myocyte survival.

J Clin Invest 2016 Feb;126(2):560-70

The maintenance of skeletal muscle mass is critical for sustaining health; however, the mechanisms responsible for muscle loss with aging and chronic diseases, such as diabetes and obesity, are poorly understood. We found that expression of a member of the AMPK-related kinase family, the SNF1-AMPK-related kinase (SNARK, also known as NUAK2), increased with muscle cell differentiation. SNARK expression increased in skeletal muscles from young mice exposed to metabolic stress and in muscles from healthy older human subjects. The regulation of SNARK expression in muscle with differentiation and physiological stress suggests that SNARK may function in the maintenance of muscle mass. Consistent with this hypothesis, decreased endogenous SNARK expression (using siRNA) in cultured muscle cells resulted in increased apoptosis and decreased cell survival under conditions of metabolic stress. Likewise, muscle-specific transgenic animals expressing a SNARK dominant-negative inactive mutant (SDN) had increased myonuclear apoptosis and activation of apoptotic mediators in muscle. Moreover, animals expressing SDN had severe, age-accelerated muscle atrophy and increased adiposity, consistent with sarcopenic obesity. Reduced SNARK activity, in vivo and in vitro, caused downregulation of the Rho kinase signaling pathway, a key mediator of cell survival. These findings reveal a critical role for SNARK in myocyte survival and the maintenance of muscle mass with age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1172/JCI79197DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4731174PMC
February 2016

Contraction stimulates muscle glucose uptake independent of atypical PKC.

Physiol Rep 2015 Nov;3(11)

Harvard Medical School, Joslin Diabetes Center, Boston, Massachusetts

Exercise 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-ζ(WT)), or an enzymatically inactive T410A-PKC-ζ mutant (PKC-ζ(T410A)). We also studied skeletal muscle-specific PKC-λ knockout (MλKO) mice. Basal glucose uptake was similar between WT, PKC-ζ(WT), and PKC-ζ(T410A) tibialis anterior muscles. In contrast, in situ contraction-stimulated glucose uptake was increased in PKC-ζ(T410A) tibialis anterior muscles compared to WT or PKC-ζ(WT) 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.14814/phy2.12565DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673624PMC
November 2015

Exercise and Regulation of Carbohydrate Metabolism.

Prog Mol Biol Transl Sci 2015 20;135:17-37. Epub 2015 Aug 20.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts, USA; Department of Medicine, Brigham, and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. Electronic address:

Carbohydrates are the preferred substrate for contracting skeletal muscles during high-intensity exercise and are also readily utilized during moderate intensity exercise. This use of carbohydrates during physical activity likely played an important role during the survival of early Homo sapiens, and genes and traits regulating physical activity, carbohydrate metabolism, and energy storage have undoubtedly been selected throughout evolution. In contrast to the life of early H. sapiens, modern lifestyles are predominantly sedentary. As a result, intake of excessive amounts of carbohydrates due to the easy and continuous accessibility to modern high-energy food and drinks has not only become unnecessary but also led to metabolic diseases in the face of physical inactivity. A resulting metabolic disease is type 2 diabetes, a complex endocrine disorder characterized by abnormally high concentrations of circulating glucose. This disease now affects millions of people worldwide. Exercise has beneficial effects to help control impaired glucose homeostasis with metabolic disease, and is a well-established tool to prevent and combat type 2 diabetes. This chapter focuses on the effects of exercise on carbohydrate metabolism in skeletal muscle and systemic glucose homeostasis. We will also focus on the molecular mechanisms that mediate the effects of exercise to increase glucose uptake in skeletal muscle. It is now well established that there are different proximal signaling pathways that mediate the effects of exercise and insulin on glucose uptake, and these distinct mechanisms are consistent with the ability of exercise to increase glucose uptake in the face of insulin resistance in people with type 2 diabetes. Ongoing research in this area is aimed at defining the precise mechanism by which exercise increases glucose uptake and insulin sensitivity and the types of exercise necessary for these important health benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/bs.pmbts.2015.07.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4727532PMC
November 2016

MicroRNA-455 regulates brown adipogenesis via a novel HIF1an-AMPK-PGC1α signaling network.

EMBO Rep 2015 Oct 24;16(10):1378-93. Epub 2015 Aug 24.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA

Brown adipose tissue (BAT) dissipates chemical energy as heat and can counteract obesity. MicroRNAs are emerging as key regulators in development and disease. Combining microRNA and mRNA microarray profiling followed by bioinformatic analyses, we identified miR-455 as a new regulator of brown adipogenesis. miR-455 exhibits a BAT-specific expression pattern and is induced by cold and the browning inducer BMP7. In vitro gain- and loss-of-function studies show that miR-455 regulates brown adipocyte differentiation and thermogenesis. Adipose-specific miR-455 transgenic mice display marked browning of subcutaneous white fat upon cold exposure. miR-455 activates AMPKα1 by targeting HIF1an, and AMPK promotes the brown adipogenic program and mitochondrial biogenesis. Concomitantly, miR-455 also targets the adipogenic suppressors Runx1t1 and Necdin, initiating adipogenic differentiation. Taken together, the data reveal a novel microRNA-regulated signaling network that controls brown adipogenesis and may be a potential therapeutic target for human metabolic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.15252/embr.201540837DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4766451PMC
October 2015

Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism.

Nat Commun 2015 Aug 24;6:8054. Epub 2015 Aug 24.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, 1 Joslin Plaza, Boston, Massachusetts 02215, USA.

Skeletal muscle is composed of both slow-twitch oxidative myofibers and fast-twitch glycolytic myofibers that differentially impact muscle metabolism, function and eventually whole-body physiology. Here we show that the mesodermal transcription factor T-box 15 (Tbx15) is highly and specifically expressed in glycolytic myofibers. Ablation of Tbx15 in vivo leads to a decrease in muscle size due to a decrease in the number of glycolytic fibres, associated with a small increase in the number of oxidative fibres. This shift in fibre composition results in muscles with slower myofiber contraction and relaxation, and also decreases whole-body oxygen consumption, reduces spontaneous activity, increases adiposity and glucose intolerance. Mechanistically, ablation of Tbx15 leads to activation of AMPK signalling and a decrease in Igf2 expression. Thus, Tbx15 is one of a limited number of transcription factors to be identified with a critical role in regulating glycolytic fibre identity and muscle metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms9054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4552045PMC
August 2015

Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis.

Cell Rep 2015 May 14;11(8):1220-35. Epub 2015 May 14.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA. Electronic address:

Insulin and insulin-like growth factor 1 (IGF-1) are major regulators of muscle protein and glucose homeostasis. To determine how these pathways interact, we generated mice with muscle-specific knockout of IGF-1 receptor (IGF1R) and insulin receptor (IR). These MIGIRKO mice showed >60% decrease in muscle mass. Despite a complete lack of insulin/IGF-1 signaling in muscle, MIGIRKO mice displayed normal glucose and insulin tolerance. Indeed, MIGIRKO mice showed fasting hypoglycemia and increased basal glucose uptake. This was secondary to decreased TBC1D1 resulting in increased Glut4 and Glut1 membrane localization. Interestingly, overexpression of a dominant-negative IGF1R in muscle induced glucose intolerance in MIGIRKO animals. Thus, loss of insulin/IGF-1 signaling impairs muscle growth, but not whole-body glucose tolerance due to increased membrane localization of glucose transporters. Nonetheless, presence of a dominant-negative receptor, even in the absence of functional IR/IGF1R, induces glucose intolerance, indicating that interactions between these receptors and other proteins in muscle can impair glucose homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2015.04.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4449334PMC
May 2015

A novel role for subcutaneous adipose tissue in exercise-induced improvements in glucose homeostasis.

Diabetes 2015 Jun 20;64(6):2002-14. Epub 2015 Jan 20.

Section on Integrative Physiology and Metabolism, Joslin Diabetes Center, Harvard Medical School, Boston, MA Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Exercise training improves whole-body glucose homeostasis through effects largely attributed to adaptations in skeletal muscle; however, training also affects other tissues, including adipose tissue. To determine whether exercise-induced adaptations to adipose tissue contribute to training-induced improvements in glucose homeostasis, subcutaneous white adipose tissue (scWAT) from exercise-trained or sedentary donor mice was transplanted into the visceral cavity of sedentary recipients. Remarkably, 9 days post-transplantation, mice receiving scWAT from exercise-trained mice had improved glucose tolerance and enhanced insulin sensitivity compared with mice transplanted with scWAT from sedentary or sham-treated mice. Mice transplanted with scWAT from exercise-trained mice had increased insulin-stimulated glucose uptake in tibialis anterior and soleus muscles and brown adipose tissue, suggesting that the transplanted scWAT exerted endocrine effects. Furthermore, the deleterious effects of high-fat feeding on glucose tolerance and insulin sensitivity were completely reversed if high-fat-fed recipient mice were transplanted with scWAT from exercise-trained mice. In additional experiments, voluntary exercise training by wheel running for only 11 days resulted in profound changes in scWAT, including the increased expression of ∼1,550 genes involved in numerous cellular functions including metabolism. Exercise training causes adaptations to scWAT that elicit metabolic improvements in other tissues, demonstrating a previously unrecognized role for adipose tissue in the beneficial effects of exercise on systemic glucose homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/db14-0704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4439563PMC
June 2015