Publications by authors named "Brian G Drew"

51 Publications

Integrative analysis of the plasma proteome and polygenic risk of cardiometabolic diseases.

Nat Metab 2021 Nov 8;3(11):1476-1483. Epub 2021 Nov 8.

Cambridge Baker Systems Genomics Initiative, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Cardiometabolic diseases are frequently polygenic in architecture, comprising a large number of risk alleles with small effects spread across the genome. Polygenic scores (PGS) aggregate these into a metric representing an individual's genetic predisposition to disease. PGS have shown promise for early risk prediction and there is an open question as to whether PGS can also be used to understand disease biology. Here, we demonstrate that cardiometabolic disease PGS can be used to elucidate the proteins underlying disease pathogenesis. In 3,087 healthy individuals, we found that PGS for coronary artery disease, type 2 diabetes, chronic kidney disease and ischaemic stroke are associated with the levels of 49 plasma proteins. Associations were polygenic in architecture, largely independent of cis and trans protein quantitative trait loci and present for proteins without quantitative trait loci. Over a follow-up of 7.7 years, 28 of these proteins associated with future myocardial infarction or type 2 diabetes events, 16 of which were mediators between polygenic risk and incident disease. Twelve of these were druggable targets with therapeutic potential. Our results demonstrate the potential for PGS to uncover causal disease biology and targets with therapeutic potential, including those that may be missed by approaches utilizing information at a single locus.
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http://dx.doi.org/10.1038/s42255-021-00478-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8574944PMC
November 2021

SOD2 in skeletal muscle: New insights from an inducible deletion model.

Redox Biol 2021 11 14;47:102135. Epub 2021 Sep 14.

Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Melbourne, Australia. Electronic address:

Metabolic conditions such as obesity, insulin resistance and glucose intolerance are frequently associated with impairments in skeletal muscle function and metabolism. This is often linked to dysregulation of homeostatic pathways including an increase in reactive oxygen species (ROS) and oxidative stress. One of the main sites of ROS production is the mitochondria, where the flux of substrates through the electron transport chain (ETC) can result in the generation of oxygen free radicals. Fortunately, several mechanisms exist to buffer bursts of intracellular ROS and peroxide production, including the enzymes Catalase, Glutathione Peroxidase and Superoxide Dismutase (SOD). Of the latter, there are two intracellular isoforms; SOD1 which is mostly cytoplasmic, and SOD2 which is found exclusively in the mitochondria. Developmental and chronic loss of these enzymes has been linked to disease in several studies, however the temporal effects of these disturbances remain largely unexplored. Here, we induced a post-developmental (8-week old mice) deletion of SOD2 in skeletal muscle (SOD2-iMKO) and demonstrate that 16 weeks of SOD2 deletion leads to no major impairment in whole body metabolism, despite these mice displaying alterations in aspects of mitochondrial abundance and voluntary ambulatory movement. This is likely partly explained by the suggestive data that a compensatory response may exist from other redox enzymes, including catalase and glutathione peroxidases. Nevertheless, we demonstrated that inducible SOD2 deletion impacts on specific aspects of muscle lipid metabolism, including the abundance of phospholipids and phosphatidic acid (PA), the latter being a key intermediate in several cellular signaling pathways. Thus, our findings suggest that post-developmental deletion of SOD2 induces a more subtle phenotype than previous embryonic models have shown, allowing us to highlight a previously unrecognized link between SOD2, mitochondrial function and bioactive lipid species including PA.
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http://dx.doi.org/10.1016/j.redox.2021.102135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487078PMC
November 2021

Lipin 1 modulates mRNA splicing during fasting adaptation in liver.

JCI Insight 2021 09 8;6(17). Epub 2021 Sep 8.

Human Genetics, David Geffen School of Medicine at UCLA,

Lipin 1 regulates cellular lipid homeostasis through roles in glycerolipid synthesis (through phosphatidic acid phosphatase activity) and transcriptional coactivation. Lipin 1-deficient individuals exhibit episodic disease symptoms that are triggered by metabolic stress, such as stress caused by prolonged fasting. We sought to identify critical lipin 1 activities during fasting. We determined that lipin 1 deficiency induces widespread alternative mRNA splicing in liver during fasting, much of which is normalized by refeeding. The role of lipin 1 in mRNA splicing was largely independent of its enzymatic function. We identified interactions between lipin 1 and spliceosome proteins, as well as a requirement for lipin 1 to maintain homeostatic levels of spliceosome small nuclear RNAs and specific RNA splicing factors. In fasted Lpin1-/- liver, we identified a correspondence between alternative splicing of phospholipid biosynthetic enzymes and dysregulated phospholipid levels; splicing patterns and phospholipid levels were partly normalized by feeding. Thus, lipin 1 influences hepatic lipid metabolism through mRNA splicing, as well as through enzymatic and transcriptional activities, and fasting exacerbates the deleterious effects of lipin 1 deficiency on metabolic homeostasis.
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http://dx.doi.org/10.1172/jci.insight.150114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492312PMC
September 2021

FXR activation protects against NAFLD via bile-acid-dependent reductions in lipid absorption.

Cell Metab 2021 Aug 15;33(8):1671-1684.e4. Epub 2021 Jul 15.

Department of Medicine, Division of Cardiology, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Department of Biological Chemistry, David Geffen School of Medicine, University of California, Los Angeles (UCLA), Los Angeles, CA, USA; Jonsson Comprehensive Cancer Center (JCCC), UCLA, Los Angeles, CA, USA; Molecular Biology Institute, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. Electronic address:

FXR agonists are used to treat non-alcoholic fatty liver disease (NAFLD), in part because they reduce hepatic lipids. Here, we show that FXR activation with the FXR agonist GSK2324 controls hepatic lipids via reduced absorption and selective decreases in fatty acid synthesis. Using comprehensive lipidomic analyses, we show that FXR activation in mice or humans specifically reduces hepatic levels of mono- and polyunsaturated fatty acids (MUFA and PUFA). Decreases in MUFA are due to FXR-dependent repression of Scd1, Dgat2, and Lpin1 expression, which is independent of SHP and SREBP1c. FXR-dependent decreases in PUFAs are mediated by decreases in lipid absorption. Replenishing bile acids in the diet prevented decreased lipid absorption in GSK2324-treated mice, suggesting that FXR reduces absorption via decreased bile acids. We used tissue-specific FXR KO mice to show that hepatic FXR controls lipogenic genes, whereas intestinal FXR controls lipid absorption. Together, our studies establish two distinct pathways by which FXR regulates hepatic lipids.
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http://dx.doi.org/10.1016/j.cmet.2021.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353952PMC
August 2021

Tissue-specific expression of Cas9 has no impact on whole-body metabolism in four transgenic mouse lines.

Mol Metab 2021 Nov 8;53:101292. Epub 2021 Jul 8.

Baker Heart & Diabetes Institute, Melbourne, 3004, Australia; Baker Department of Cardiometabolic Health, The University of Melbourne, Melbourne, Australia; Central Clinical School, Monash University, Melbourne, 3004, Australia. Electronic address:

Objective: CRISPR/Cas9 technology has revolutionized gene editing and fast tracked our capacity to manipulate genes of interest for the benefit of both research and therapeutic applications. Whilst many advances have, and continue to be made in this area, perhaps the most utilized technology to date has been the generation of knockout cells, tissues and animals. The advantages of this technology are many fold, however some questions still remain regarding the effects that long term expression of foreign proteins such as Cas9, have on mammalian cell function. Several studies have proposed that chronic overexpression of Cas9, with or without its accompanying guide RNAs, may have deleterious effects on cell function and health. This is of particular concern when applying this technology in vivo, where chronic expression of Cas9 in tissues of interest may promote disease-like phenotypes and thus confound the investigation of the effects of the gene of interest. Although these concerns remain valid, no study to our knowledge has yet to demonstrate this directly.

Methods: In this study we used the lox-stop-lox (LSL) spCas9 ROSA26 transgenic (Tg) mouse line to generate four tissue-specific Cas9-Tg models that express Cas9 in the heart, liver, skeletal muscle or adipose tissue. We performed comprehensive phenotyping of these mice up to 20-weeks of age and subsequently performed molecular analysis of their organs.

Results: We demonstrate that Cas9 expression in these tissues had no detrimental effect on whole body health of the animals, nor did it induce any tissue-specific effects on whole body energy metabolism, liver health, inflammation, fibrosis, heart function or muscle mass.

Conclusions: Our data suggests that these models are suitable for studying the tissue specific effects of gene deletion using the LSL-Cas9-Tg model, and that phenotypes observed utilizing these models can be confidently interpreted as being gene specific, and not confounded by the chronic overexpression of Cas9.
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http://dx.doi.org/10.1016/j.molmet.2021.101292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361256PMC
November 2021

Genome-Wide Association Study Identifies a Functional Variant Associated With HDL-C (High-Density Lipoprotein Cholesterol) Levels and Premature Coronary Artery Disease.

Arterioscler Thromb Vasc Biol 2021 09 8;41(9):2494-2508. Epub 2021 Jul 8.

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia (A.C.C., B.G.D.).

Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population.

Approach And Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism.

Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.
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http://dx.doi.org/10.1161/ATVBAHA.120.315391DOI Listing
September 2021

Loss of the long non-coding RNA OIP5-AS1 exacerbates heart failure in a sex-specific manner.

iScience 2021 Jun 13;24(6):102537. Epub 2021 May 13.

Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia.

Long non-coding RNAs (lncRNAs) have been demonstrated to influence numerous biological processes, being strongly implicated in the maintenance and physiological function of various tissues including the heart. The lncRNA OIP5-AS1 (/C) has been studied in several settings; however its role in cardiac pathologies remains mostly uncharacterized. Using a series of and methods, we demonstrate that OIP5-AS1 is regulated during cardiac development in rodent and human models and in disease settings in mice. Using CRISPR, we engineered a global OIP5-AS1 knockout (KO) mouse and demonstrated that female KO mice develop exacerbated heart failure following cardiac pressure overload (transverse aortic constriction [TAC]) but male mice do not. RNA-sequencing of wild-type and KO hearts suggest that OIP5-AS1 regulates pathways that impact mitochondrial function. Thus, these findings highlight OIP5-AS1 as a gene of interest in sex-specific differences in mitochondrial function and development of heart failure.
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http://dx.doi.org/10.1016/j.isci.2021.102537DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184514PMC
June 2021

Deletion of Trim28 in committed adipocytes promotes obesity but preserves glucose tolerance.

Nat Commun 2021 01 4;12(1):74. Epub 2021 Jan 4.

Baker Heart & Diabetes Institute, Melbourne, VIC, Australia, 3004.

The effective storage of lipids in white adipose tissue (WAT) critically impacts whole body energy homeostasis. Many genes have been implicated in WAT lipid metabolism, including tripartite motif containing 28 (Trim28), a gene proposed to primarily influence adiposity via epigenetic mechanisms in embryonic development. However, in the current study we demonstrate that mice with deletion of Trim28 specifically in committed adipocytes, also develop obesity similar to global Trim28 deletion models, highlighting a post-developmental role for Trim28. These effects were exacerbated in female mice, contributing to the growing notion that Trim28 is a sex-specific regulator of obesity. Mechanistically, this phenotype involves alterations in lipolysis and triglyceride metabolism, explained in part by loss of Klf14 expression, a gene previously demonstrated to modulate adipocyte size and body composition in a sex-specific manner. Thus, these findings provide evidence that Trim28 is a bona fide, sex specific regulator of post-developmental adiposity and WAT function.
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http://dx.doi.org/10.1038/s41467-020-20434-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782476PMC
January 2021

Concordant peripheral lipidome signatures in two large clinical studies of Alzheimer's disease.

Nat Commun 2020 11 10;11(1):5698. Epub 2020 Nov 10.

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

Changes to lipid metabolism are tightly associated with the onset and pathology of Alzheimer's disease (AD). Lipids are complex molecules comprising many isomeric and isobaric species, necessitating detailed analysis to enable interpretation of biological significance. Our expanded targeted lipidomics platform (569 species across 32 classes) allows for detailed lipid separation and characterisation. In this study we examined peripheral samples of two cohorts (AIBL, n = 1112 and ADNI, n = 800). We are able to identify concordant peripheral signatures associated with prevalent AD arising from lipid pathways including; ether lipids, sphingolipids (notably GM gangliosides) and lipid classes previously associated with cardiometabolic disease (phosphatidylethanolamine and triglycerides). We subsequently identified similar lipid signatures in both cohorts with future disease. Lastly, we developed multivariate lipid models that improved classification and prediction. Our results provide a holistic view between the lipidome and AD using a comprehensive approach, providing targets for further mechanistic investigation.
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http://dx.doi.org/10.1038/s41467-020-19473-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7655942PMC
November 2020

Apo AI Nanoparticles Delivered Post Myocardial Infarction Moderate Inflammation.

Circ Res 2020 11 21;127(11):1422-1436. Epub 2020 Sep 21.

Baker Heart and Diabetes Institute, Melbourne, Australia (A.L.R., M.R., M.K., A.L.N., S.E.H., G.L.L., A.J.M., B.G.D., B.A.K.).

Rationale: Decades of research have examined immune-modulatory strategies to protect the heart after an acute myocardial infarction and prevent progression to heart failure but have failed to translate to clinical benefit.

Objective: To determine anti-inflammatory actions of n-apo AI (Apo AI nanoparticles) that contribute to cardiac tissue recovery after myocardial infarction.

Methods And Results: Using a preclinical mouse model of myocardial infarction, we demonstrate that a single intravenous bolus of n-apo AI (CSL111, 80 mg/kg) delivered immediately after reperfusion reduced the systemic and cardiac inflammatory response. N-apo AI treatment lowered the number of circulating leukocytes by 30±7% and their recruitment into the ischemic heart by 25±10% (all <5.0×10). This was associated with a reduction in plasma levels of the clinical biomarker of cardiac injury, cardiac troponin-I, by 52±17% (=1.01×10). N-apo AI reduced the cardiac expression of chemokines that attract neutrophils and monocytes by 60% to 80% and lowered surface expression of integrin CD11b on monocytes by 20±5% (all <5.0×10). Fluorescently labeled n-apo AI entered the infarct and peri-infarct regions and colocalized with cardiomyocytes undergoing apoptosis and with leukocytes. We further demonstrate that n-apo AI binds to neutrophils and monocytes, with preferential binding to the proinflammatory monocyte subtype and partially via SR-BI (scavenger receptor BI). In patients with type 2 diabetes, we also observed that intravenous infusion of the same n-apo AI (CSL111, 80 mg/kg) similarly reduced the level of circulating leukocytes by 12±5% (all <5.0×10).

Conclusions: A single intravenous bolus of n-apo AI delivered immediately post-myocardial infarction reduced the systemic and cardiac inflammatory response through direct actions on both the ischemic myocardium and leukocytes. These data highlight the anti-inflammatory effects of n-apo AI and provide preclinical support for investigation of its use for management of acute coronary syndromes in the setting of primary percutaneous coronary interventions.
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http://dx.doi.org/10.1161/CIRCRESAHA.120.316848DOI Listing
November 2020

Estrogen receptor α controls metabolism in white and brown adipocytes by regulating and mitochondrial remodeling.

Sci Transl Med 2020 08;12(555)

Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.

Obesity is heightened during aging, and although the estrogen receptor α (ERα) has been implicated in the prevention of obesity, its molecular actions in adipocytes remain inadequately understood. Here, we show that adipose tissue expression inversely associated with adiposity and positively associated with genes involved in mitochondrial metabolism and markers of metabolic health in 700 Finnish men and 100 strains of inbred mice from the UCLA Hybrid Mouse Diversity Panel. To determine the anti-obesity actions of ERα in fat, we selectively deleted from white and brown adipocytes in mice. In white adipose tissue, controlled oxidative metabolism by restraining the targeted elimination of mitochondria via the E3 ubiquitin ligase parkin. mtDNA content was elevated, and adipose tissue mass was reduced in adipose-selective parkin knockout mice. In brown fat centrally involved in body temperature maintenance, was requisite for both mitochondrial remodeling by dynamin-related protein 1 (Drp1) and uncoupled respiration thermogenesis by uncoupled protein 1 (Ucp1). In both white and brown fat of female mice and adipocytes in culture, mitochondrial dysfunction in the context of deletion was paralleled by a reduction in the expression of the mtDNA polymerase γ subunit We identified as an ERα target gene by showing that ERα binds the promoter to control its expression in 3T3L1 adipocytes. These findings support strategies leveraging ERα action on mitochondrial function in adipocytes to combat obesity and metabolic dysfunction.
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http://dx.doi.org/10.1126/scitranslmed.aax8096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8212422PMC
August 2020

Reducing hepatic PKD activity lowers circulating VLDL cholesterol.

J Endocrinol 2020 09;246(3):265-276

Institute for Mental and Physical Health and Clinical Translation (iMPACT) and Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Victoria, Australia.

Protein kinase D (PKD) is emerging as an important kinase regulating energy balance and glucose metabolism; however, whether hepatic PKD activity can be targeted to regulate these processes is currently unclear. In this study, hepatic PKD activity was reduced using adeno-associated virus vectors to express a dominant-negative (DN) version of PKD1, which impairs the action of all three PKD isoforms. In chow-fed mice, hepatic DN PKD expression increased whole-body glucose oxidation, but had only mild effects on glucose and insulin tolerance and no effects on glucose homeostasis following fasting and refeeding. However, circulating VLDL cholesterol was reduced under these conditions and was associated with hepatic fatty acid accumulation, but not lipids involved in lipoprotein synthesis. The limited effects on glucose homeostasis in DN PKD mice was despite reduced expression of gluconeogenic genes under both fasted and refed conditions, and enhanced pyruvate tolerance. The requirement for PKD for gluconeogenic capacity was supported by in vitro studies in cultured FAO hepatoma cells expressing DN PKD, which produced less glucose under basal conditions. Although these pathways are increased in obesity, the expression of DN PKD in the liver of mice fed a high-fat diet had no impact on glucose tolerance, insulin action, pyruvate tolerance or plasma VLDL. Together, these data suggest that PKD signalling in the liver regulates metabolic pathways involved in substrate redistribution under conditions of normal nutrient availability, but not under conditions of overnutrition such as in obesity.
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http://dx.doi.org/10.1530/JOE-19-0548DOI Listing
September 2020

Relationships Between Plasma Lipids Species, Gender, Risk Factors, and Alzheimer's Disease.

J Alzheimers Dis 2020 ;76(1):303-315

School of Medical and Health Sciences, Edith Cowan University, Joondalup, Western Australia, WA, Australia.

Background: Lipid metabolism is altered in Alzheimer's disease (AD); however, the relationship between AD risk factors (age, APOEɛ4, and gender) and lipid metabolism is not well defined.

Objective: We investigated whether altered lipid metabolism associated with increased age, gender, and APOE status may contribute to the development of AD by examining these risk factors in healthy controls and also clinically diagnosed AD individuals.

Methods: We performed plasma lipidomic profiling (582 lipid species) of the Australian Imaging, Biomarkers and Lifestyle flagship study of aging cohort (AIBL) using liquid chromatography-mass spectrometry. Linear regression and interaction analysis were used to explore the relationship between risk factors and plasma lipid species.

Results: We observed strong associations between plasma lipid species with gender and increasing age in cognitively normal individuals. However, APOEɛ4 was relatively weakly associated with plasma lipid species. Interaction analysis identified differential associations of sphingolipids and polyunsaturated fatty acid esterified lipid species with AD based on age and gender, respectively. These data indicate that the risk associated with age, gender, and APOEɛ4 may, in part, be mediated by changes in lipid metabolism.

Conclusion: This study extends our existing knowledge of the relationship between the lipidome and AD and highlights the complexity of the relationships between lipid metabolism and AD at different ages and between men and women. This has important implications for how we assess AD risk and also for potential therapeutic strategies involving modulation of lipid metabolic pathways.
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http://dx.doi.org/10.3233/JAD-191304DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7369125PMC
May 2021

The Antioxidant Moiety of MitoQ Imparts Minimal Metabolic Effects in Adipose Tissue of High Fat Fed Mice.

Front Physiol 2019 8;10:543. Epub 2019 May 8.

Baker Heart and Diabetes Institute, Melbourne, VIC, Australia.

Mitochondrial dysfunction is associated with a diverse array of diseases ranging from dystrophy and heart failure to obesity and hepatosteatosis. One of the major biochemical consequences of impaired mitochondrial function is an accumulation of mitochondrial superoxide, or reactive oxygen species (ROS). Excessive ROS can be detrimental to cellular health and is proposed to underpin many mitochondrial diseases. Accordingly, much research has been committed to understanding ways to therapeutically prevent and reduce ROS accumulation. In white adipose tissue (WAT), ROS is associated with obesity and its subsequent complications, and thus reducing mitochondrial ROS may represent a novel strategy for treating obesity related disorders. One therapeutic approach employed to reduce ROS abundance is the mitochondrial-targeted coenzyme Q (MitoQ), which enables mitochondrial specific delivery of a CoQ10 antioxidant via its triphenylphosphonium bromide (TPP+) cation. Indeed, MitoQ has been successfully shown to accumulate at the outer mitochondrial membrane and prevent ROS accumulation in several tissues ; however, the specific effects of MitoQ on adipose tissue metabolism have not been studied. Here we demonstrate that mice fed high-fat diet with concomitant administration of MitoQ, exhibit minimal metabolic benefit in adipose tissue. We also demonstrate that both MitoQ and its control agent dTPP+ had significant and equivalent effects on whole-body metabolism, suggesting that the dTPP+ cation rather than the antioxidant moiety, was responsible for these changes. These findings have important implications for future studies using MitoQ and other TPP+ compounds.
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http://dx.doi.org/10.3389/fphys.2019.00543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517842PMC
May 2019

An integrative systems genetic analysis of mammalian lipid metabolism.

Nature 2019 03 27;567(7747):187-193. Epub 2019 Feb 27.

Central Clinical School, Department of Medicine, Monash University, Melbourne, Victoria, Australia.

Dysregulation of lipid homeostasis is a precipitating event in the pathogenesis and progression of hepatosteatosis and metabolic syndrome. These conditions are highly prevalent in developed societies and currently have limited options for diagnostic and therapeutic intervention. Here, using a proteomic and lipidomic-wide systems genetic approach, we interrogated lipid regulatory networks in 107 genetically distinct mouse strains to reveal key insights into the control and network structure of mammalian lipid metabolism. These include the identification of plasma lipid signatures that predict pathological lipid abundance in the liver of mice and humans, defining subcellular localization and functionality of lipid-related proteins, and revealing functional protein and genetic variants that are predicted to modulate lipid abundance. Trans-omic analyses using these datasets facilitated the identification and validation of PSMD9 as a previously unknown lipid regulatory protein. Collectively, our study serves as a rich resource for probing mammalian lipid metabolism and provides opportunities for the discovery of therapeutic agents and biomarkers in the setting of hepatic lipotoxicity.
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http://dx.doi.org/10.1038/s41586-019-0984-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656374PMC
March 2019

The E3 ligase MARCH5 is a PPARγ target gene that regulates mitochondria and metabolism in adipocytes.

Am J Physiol Endocrinol Metab 2019 02 4;316(2):E293-E304. Epub 2018 Dec 4.

Baker Heart and Diabetes Institute , Melbourne, Victoria , Australia.

Mitochondrial dynamics refers to the constant remodeling of mitochondrial populations by multiple cellular pathways that help maintain mitochondrial health and function. Disruptions in mitochondrial dynamics often lead to mitochondrial dysfunction, which is frequently associated with disease in rodents and humans. Consistent with this, obesity is associated with reduced mitochondrial function in white adipose tissue, partly via alterations in mitochondrial dynamics. Several proteins, including the E3 ubiquitin ligase membrane-associated RING-CH-type finger 5 (MARCH5), are known to regulate mitochondrial dynamics; however, the role of these proteins in adipocytes has been poorly studied. Here, we show that MARCH5 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ) during adipogenesis and is correlated with fat mass across a panel of genetically diverse mouse strains, in ob/ob mice, and in humans. Furthermore, manipulation of MARCH5 expression in vitro and in vivo alters mitochondrial function, affects cellular metabolism, and leads to differential regulation of several metabolic genes. Thus our data demonstrate an association between mitochondrial dynamics and metabolism that defines MARCH5 as a critical link between these interconnected pathways.
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http://dx.doi.org/10.1152/ajpendo.00394.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397360PMC
February 2019

High-Throughput Plasma Lipidomics: Detailed Mapping of the Associations with Cardiometabolic Risk Factors.

Cell Chem Biol 2019 01 8;26(1):71-84.e4. Epub 2018 Nov 8.

Head Metabolomics Laboratory, Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia; Faculty of Medicine, Nursing and Health Sciences, Monash University, Melbourne, Australia. Electronic address:

High-throughput targeted lipid profiling with liquid chromatography-mass spectrometry (LC-MS) has been used extensively to identify associations between plasma lipid species and disease states. Such methods, used to characterize larger clinical cohorts, often suffer from an inability to differentiate isomeric forms of glycerophospholipids that are typically reported as the sum fatty acid carbons and double bonds. Here we report a chromatography gradient coupled with a detailed characterization of the human plasma lipidome to provide improved resolution and identification of 636 lipid species, including previously unreported species, in a 15-min analysis. We have utilized this method on a subset of the Australian Diabetes, Obesity, and Lifestyle Study and have detailed associations of plasma lipid species with anthropometric and blood glucose measures. These results highlight the importance and power of high-throughput lipidomics coupled with a detailed characterization of the lipidome to better understand lipid biology in a population setting.
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http://dx.doi.org/10.1016/j.chembiol.2018.10.008DOI Listing
January 2019

The impact of ERα action on muscle metabolism and insulin sensitivity - Strong enough for a man, made for a woman.

Mol Metab 2018 09 21;15:20-34. Epub 2018 Jun 21.

Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA, 90095, USA.

Background: The incidence of chronic disease is elevated in women after menopause. Natural variation in muscle expression of the estrogen receptor (ER)α is inversely associated with plasma insulin and adiposity. Moreover, reduced muscle ERα expression levels are observed in women and animals presenting clinical features of the metabolic syndrome (MetSyn). Considering that metabolic dysfunction impacts nearly a quarter of the U.S. adult population and elevates chronic disease risk including type 2 diabetes, heart disease, and certain cancers, treatment strategies to combat metabolic dysfunction and associated pathologies are desperately needed.

Scope Of The Review: This review will provide evidence supporting a critical and protective role for skeletal muscle ERα in the regulation of metabolic homeostasis and insulin sensitivity, and propose novel ERα targets involved in the maintenance of metabolic health.

Major Conclusions: Studies identifying ERα-regulated pathways essential for disease prevention will lay the important foundation for the rational design of novel therapeutics to improve the metabolic health of women while limiting secondary complications that have plagued traditional hormone replacement interventions.
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http://dx.doi.org/10.1016/j.molmet.2018.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066787PMC
September 2018

Skeletal muscle-specific overexpression of heat shock protein 72 improves skeletal muscle insulin-stimulated glucose uptake but does not alter whole body metabolism.

Diabetes Obes Metab 2018 08 3;20(8):1928-1936. Epub 2018 May 3.

Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia.

Aims: The induction of heat shock protein 72 (Hsp72) via heating, genetic manipulation or pharmacological activation is metabolically protective in the setting of obesity-induced insulin resistance across mammalian species. In this study, we set out to determine whether the overexpression of Hsp72, specifically in skeletal muscle, can protect against high-fat diet (HFD)-induced obesity and insulin resistance.

Materials And Methods: An Adeno-Associated Viral vector (AAV), designed to overexpress Hsp72 in skeletal muscle only, was used to study the effects of increasing Hsp72 levels on various metabolic parameters. Two studies were conducted, the first with direct intramuscular (IM) injection of the AAV:Hsp72 into the tibialis anterior hind-limb muscle and the second with a systemic injection to enable body-wide skeletal muscle transduction.

Results: IM injection of the AAV:Hsp72 significantly improved skeletal muscle insulin-stimulated glucose clearance in treated hind-limb muscles, as compared with untreated muscles of the contralateral leg when mice were fed an HFD. Despite this finding, systemic administration of AAV:Hsp72 did not improve body composition parameters such as body weight, fat mass or percentage body fat, nor did it lead to an improvement in fasting glucose levels or glucose tolerance. Furthermore, no differences were observed for other metabolic parameters such as whole-body oxygen consumption, energy expenditure or physical activity levels.

Conclusions: At the levels of Hsp72 over-expression reported herein, skeletal muscle-specific Hsp72 overexpression via IM injection has the capacity to increase insulin-stimulated glucose clearance in this muscle. However, upon systemic injection, which results in lower muscle Hsp72 overexpression, no beneficial effects on whole-body metabolism are observed.
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http://dx.doi.org/10.1111/dom.13319DOI Listing
August 2018

Mitochondrial fission protein Drp1 inhibition promotes cardiac mesodermal differentiation of human pluripotent stem cells.

Cell Death Discov 2018 Dec 5;4:39. Epub 2018 Mar 5.

1St Vincent's Institute of Medical Research, Fitzroy, VIC 3065 Australia.

Human induced pluripotent stem cells (iPSCs) are a valuable tool for studying the cardiac developmental process in vitro, and cardiomyocytes derived from iPSCs are a putative cell source for personalized medicine. Changes in mitochondrial morphology have been shown to occur during cellular reprogramming and pluripotent stem cell differentiation. However, the relationships between mitochondrial dynamics and cardiac mesoderm commitment of iPSCs remain unclear. Here we demonstrate that changes in mitochondrial morphology from a small granular fragmented phenotype in pluripotent stem cells to a filamentous reticular elongated network in differentiated cardiomyocytes are required for cardiac mesodermal differentiation. Genetic and pharmacological inhibition of the mitochondrial fission protein, Drp1, by either small interfering RNA or Mdivi-1, respectively, increased cardiac mesoderm gene expression in iPSCs. Treatment of iPSCs with Mdivi-1 during embryoid body formation significantly increased the percentage of beating embryoid bodies and expression of cardiac-specific genes. Furthermore, Drp1 gene silencing was accompanied by increased mitochondrial respiration and decreased aerobic glycolysis. Our findings demonstrate that shifting the balance of mitochondrial morphology toward fusion by inhibition of Drp1 promoted cardiac differentiation of human iPSCs with a metabolic shift from glycolysis towards oxidative phosphorylation. These findings suggest that Drp1 may represent a new molecular target for future development of strategies to promote the differentiation of human iPSCs into cardiac lineages for patient-specific cardiac regenerative medicine.
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http://dx.doi.org/10.1038/s41420-018-0042-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841367PMC
December 2018

Estrogen receptor α protects pancreatic β-cells from apoptosis by preserving mitochondrial function and suppressing endoplasmic reticulum stress.

J Biol Chem 2018 03 29;293(13):4735-4751. Epub 2018 Jan 29.

Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Los Angeles, California 90095; Iris Cantor UCLA Women's Health Research Center, Los Angeles, California 90095. Electronic address:

Estrogen receptor α (ERα) action plays an important role in pancreatic β-cell function and survival; thus, it is considered a potential therapeutic target for the treatment of type 2 diabetes in women. However, the mechanisms underlying the protective effects of ERα remain unclear. Because ERα regulates mitochondrial metabolism in other cell types, we hypothesized that ERα may act to preserve insulin secretion and promote β-cell survival by regulating mitochondrial-endoplasmic reticulum (EndoRetic) function. We tested this hypothesis using pancreatic islet-specific ERα knockout (PERαKO) mice and Min6 β-cells in culture with Esr1 knockdown (KD). We found that Esr1-KD promoted reactive oxygen species production that associated with reduced fission/fusion dynamics and impaired mitophagy. Electron microscopy showed mitochondrial enlargement and a pro-fusion phenotype. Mitochondrial cristae and endoplasmic reticulum were dilated in Esr1-KD compared with ERα replete Min6 β-cells. Increased expression of and was paralleled by increased oxygen consumption and apoptosis susceptibility in ERα-KD cells. In contrast, ERα overexpression and ligand activation reduced both and expression, likely by ERα binding to consensus estrogen-response element sites in the and promoters. Together, our findings suggest that ERα promotes β-cell survival and insulin secretion through maintenance of mitochondrial fission/fusion-mitophagy dynamics and EndoRetic function, in part by and repression.
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http://dx.doi.org/10.1074/jbc.M117.805069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5880140PMC
March 2018

The Role of Skeletal Muscle Estrogen Receptors in Metabolic Homeostasis and Insulin Sensitivity.

Adv Exp Med Biol 2017 ;1043:257-284

Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.

Women in the modern era are challenged with facing menopausal symptoms as well as heightened disease risk associated with increasing adiposity and metabolic dysfunction for up to three decades of life. Treatment strategies to combat metabolic dysfunction and associated pathologies have been hampered by our lack of understanding regarding the biological causes of these clinical conditions and our incomplete understanding regarding the effects of estrogens and the tissue-specific functions and molecular actions of its receptors. In this chapter we provide evidence supporting a critical and protective role for skeletal muscle estrogen receptor α in the maintenance of metabolic homeostasis and insulin sensitivity. Studies identifying the critical ER-regulated pathways essential for disease prevention will lay the important foundation for the rational design of novel therapeutic strategies to improve the health of women while limiting secondary complications that have plagued traditional hormone replacement interventions.
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http://dx.doi.org/10.1007/978-3-319-70178-3_13DOI Listing
June 2018

Mdivi-1 Protects Human W8B2 Cardiac Stem Cells from Oxidative Stress and Simulated Ischemia-Reperfusion Injury.

Stem Cells Dev 2017 12 27;26(24):1771-1780. Epub 2017 Nov 27.

1 St Vincent's Institute of Medical Research , Fitzroy, Australia .

Cardiac stem cell (CSC) therapy is a promising approach to treat ischemic heart disease. However, the poor survival of transplanted stem cells in the ischemic myocardium has been a major impediment in achieving an effective cell-based therapy against myocardial infarction. Inhibiting mitochondrial fission has been shown to promote survival of several cell types. However, the role of mitochondrial morphology in survival of human CSC remains unknown. In this study, we investigated whether mitochondrial division inhibitor-1 (Mdivi-1), an inhibitor of mitochondrial fission protein dynamin-related protein-1 (Drp1), can improve survival of a novel population of human W8B2 CSCs in hydrogen peroxide (HO)-induced oxidative stress and simulated ischemia-reperfusion injury models. Mdivi-1 significantly reduced HO-induced cell death in a dose-dependent manner. This cytoprotective effect was accompanied by an increased proportion of cells with tubular mitochondria, but independent of mitochondrial membrane potential recovery and reduction of mitochondrial superoxide production. In simulated ischemia-reperfusion injury model, Mdivi-1 given as a pretreatment or throughout ischemia-reperfusion injury significantly reduced cell death. However, the cytoprotective effect of Mdivi-1 was not observed when given at reperfusion. Moreover, the cytoprotective effect of Mdivi-1 in the simulated ischemia-reperfusion injury model was not accompanied by changes in mitochondrial morphology, mitochondrial membrane potential, or mitochondrial reactive oxygen species production. Mdivi-1 also did not affect mitochondrial bioenergetics of intact W8B2 CSCs. Taken together, these experiments demonstrated that Mdivi-1 treatment of human W8B2 CSCs enhances their survival and can be employed to improve therapeutic efficacy of CSCs for ischemic heart disease.
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http://dx.doi.org/10.1089/scd.2017.0157DOI Listing
December 2017

Long non-coding RNAs (lncRNAs) in skeletal and cardiac muscle: potential therapeutic and diagnostic targets?

Clin Sci (Lond) 2016 12;130(24):2245-2256

Diabetes & Dyslipidaemia Laboratory, BakerIDI Heart & Diabetes Institute, Melbourne, Victoria 3004, Australia

The recent discovery that thousands of RNAs are transcribed by the cell but are never translated into protein, highlights a significant void in our current understanding of how transcriptional networks regulate cellular function. This is particularly astounding when we consider that over 75% of the human genome is transcribed into RNA, but only approximately 2% of RNA is translated into known proteins. This raises the question as to what function the other so-called 'non-coding RNAs' (ncRNAs) are performing in the cell. Over the last decade, an enormous amount of research has identified several classes of ncRNAs, predominantly short ncRNAs (<200 nt) that have been confirmed to have functional significance. Recent advances in sequencing technology and bioinformatics have also allowed for the identification of a novel class of ncRNAs, termed long ncRNA (lncRNA) (>200 nt). Several studies have recently shown that long non-coding RNAs (lncRNAs) are associated with tissue development and disease, particularly in cell types that undergo differentiation such as stem cells, cancer cells and striated muscle (skeletal/cardiac). Therefore, understanding the function of these lncRNAs and designing strategies to detect and manipulate them, may present novel therapeutic and diagnostic opportunities. This review will explore the current literature on lncRNAs in skeletal and cardiac muscle and discuss their recent implication in development and disease. Lastly, we will also explore the possibility of using lncRNAs as therapeutic and diagnostic tools and discuss the opportunities and potential shortcomings to these applications.
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http://dx.doi.org/10.1042/CS20160244DOI Listing
December 2016

Maternal obesity reduces oxidative capacity in fetal skeletal muscle of Japanese macaques.

JCI Insight 2016 Oct 6;1(16):e86612. Epub 2016 Oct 6.

Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA.

Maternal obesity is proposed to alter the programming of metabolic systems in the offspring, increasing the risk for developing metabolic diseases; however, the cellular mechanisms remain poorly understood. Here, we used a nonhuman primate model to examine the impact of a maternal Western-style diet (WSD) alone, or in combination with obesity (Ob/WSD), on fetal skeletal muscle metabolism studied in the early third trimester. We find that fetal muscle responds to Ob/WSD by upregulating fatty acid metabolism, mitochondrial complex activity, and metabolic switches (CPT-1, PDK4) that promote lipid utilization over glucose oxidation. Ob/WSD fetuses also had reduced mitochondrial content, diminished oxidative capacity, and lower mitochondrial efficiency in muscle. The decrease in oxidative capacity and glucose metabolism was persistent in primary myotubes from Ob/WSD fetuses despite no additional lipid-induced stress. Switching obese mothers to a healthy diet prior to pregnancy did not improve fetal muscle mitochondrial function. Lastly, while maternal WSD alone led only to intermediary changes in fetal muscle metabolism, it was sufficient to increase oxidative damage and cellular stress. Our findings suggest that maternal obesity or WSD, alone or in combination, leads to programmed decreases in oxidative metabolism in offspring muscle. These alterations may have important implications for future health.
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http://dx.doi.org/10.1172/jci.insight.86612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053156PMC
October 2016

Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females.

Sci Transl Med 2016 Apr;8(334):334ra54

Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University of Copenhagen, Copenhagen 2200, Denmark.

Impaired estrogen receptor α (ERα) action promotes obesity and metabolic dysfunction in humans and mice; however, the mechanisms underlying these phenotypes remain unknown. Considering that skeletal muscle is a primary tissue responsible for glucose disposal and oxidative metabolism, we established that reduced ERα expression in muscle is associated with glucose intolerance and adiposity in women and female mice. To test this relationship, we generated muscle-specific ERα knockout (MERKO) mice. Impaired glucose homeostasis and increased adiposity were paralleled by diminished muscle oxidative metabolism and bioactive lipid accumulation in MERKO mice. Aberrant mitochondrial morphology, overproduction of reactive oxygen species, and impairment in basal and stress-induced mitochondrial fission dynamics, driven by imbalanced protein kinase A-regulator of calcineurin 1-calcineurin signaling through dynamin-related protein 1, tracked with reduced oxidative metabolism in MERKO muscle. Although muscle mitochondrial DNA (mtDNA) abundance was similar between the genotypes, ERα deficiency diminished mtDNA turnover by a balanced reduction in mtDNA replication and degradation. Our findings indicate the retention of dysfunctional mitochondria in MERKO muscle and implicate ERα in the preservation of mitochondrial health and insulin sensitivity as a defense against metabolic disease in women.
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http://dx.doi.org/10.1126/scitranslmed.aad3815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4934679PMC
April 2016

Deficiency in Apoptosis-Inducing Factor Recapitulates Chronic Kidney Disease via Aberrant Mitochondrial Homeostasis.

Diabetes 2016 04 28;65(4):1085-98. Epub 2016 Jan 28.

Mitochondria Laboratory, Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.

Apoptosis-inducing factor (AIF) is a mitochondrial flavoprotein with dual roles in redox signaling and programmed cell death. Deficiency in AIF is known to result in defective oxidative phosphorylation (OXPHOS), via loss of complex I activity and assembly in other tissues. Because the kidney relies on OXPHOS for metabolic homeostasis, we hypothesized that a decrease in AIF would result in chronic kidney disease (CKD). Here, we report that partial knockdown of Aif in mice recapitulates many features of CKD, in association with a compensatory increase in the mitochondrial ATP pool via a shift toward mitochondrial fusion, excess mitochondrial reactive oxygen species production, and Nox4 upregulation. However, despite a 50% lower AIF protein content in the kidney cortex, there was no loss of complex I activity or assembly. When diabetes was superimposed onto Aif knockdown, there were extensive changes in mitochondrial function and networking, which augmented the renal lesion. Studies in patients with diabetic nephropathy showed a decrease in AIF within the renal tubular compartment and lower AIFM1 renal cortical gene expression, which correlated with declining glomerular filtration rate. Lentiviral overexpression of Aif1m rescued glucose-induced disruption of mitochondrial respiration in human primary proximal tubule cells. These studies demonstrate that AIF deficiency is a risk factor for the development of diabetic kidney disease.
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http://dx.doi.org/10.2337/db15-0864DOI Listing
April 2016

The mitochondrial-derived peptide MOTS-c promotes metabolic homeostasis and reduces obesity and insulin resistance.

Cell Metab 2015 Mar;21(3):443-54

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA. Electronic address:

Mitochondria are known to be functional organelles, but their role as a signaling unit is increasingly being appreciated. The identification of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide, humanin, suggests the possible existence of additional sORFs in the mtDNA. Here we report a sORF within the mitochondrial 12S rRNA encoding a 16-amino-acid peptide named MOTS-c (mitochondrial open reading frame of the 12S rRNA-c) that regulates insulin sensitivity and metabolic homeostasis. Its primary target organ appears to be the skeletal muscle, and its cellular actions inhibit the folate cycle and its tethered de novo purine biosynthesis, leading to AMPK activation. MOTS-c treatment in mice prevented age-dependent and high-fat-diet-induced insulin resistance, as well as diet-induced obesity. These results suggest that mitochondria may actively regulate metabolic homeostasis at the cellular and organismal level via peptides encoded within their genome.
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http://dx.doi.org/10.1016/j.cmet.2015.02.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4350682PMC
March 2015

Estrogen receptor (ER)α-regulated lipocalin 2 expression in adipose tissue links obesity with breast cancer progression.

J Biol Chem 2015 Feb 2;290(9):5566-81. Epub 2014 Dec 2.

From the David Geffen School of Medicine, Department of Medicine, Division of Endocrinology, Diabetes and Hypertension, Jonsson Comprehensive Cancer Center, UCLA, Los Angeles, California 90095, Iris Cantor-UCLA Women's Health Center, Los Angeles, California 90095

Obesity is associated with increased breast cancer (BrCA) incidence. Considering that inactivation of estrogen receptor (ER)α promotes obesity and metabolic dysfunction in women and female mice, understanding the mechanisms and tissue-specific sites of ERα action to combat metabolic-related disease, including BrCA, is of clinical importance. To study the role of ERα in adipose tissue we generated fat-specific ERα knock-out (FERKO) mice. Herein we show that ERα deletion increased adipocyte size, fat pad weight, and tissue expression and circulating levels of the secreted glycoprotein, lipocalin 2 (Lcn2), an adipokine previously associated with BrCA development. Chromatin immunoprecipitation and luciferase reporter studies showed that ERα binds the Lcn2 promoter to repress its expression. Because adipocytes constitute an important cell type of the breast microenvironment, we examined the impact of adipocyte ERα deletion on cancer cell behavior. Conditioned medium from ERα-null adipocytes and medium containing pure Lcn2 increased proliferation and migration of a subset of BrCA cells in culture. The proliferative and promigratory effects of ERα-deficient adipocyte-conditioned medium on BrCA cells was reversed by Lcn2 deletion. BrCA cell responsiveness to exogenous Lcn2 was heightened in cell types where endogenous Lcn2 expression was minimal, but components of the Lcn2 signaling pathway were enriched, i.e. SLC22A17 and 3-hydroxybutyrate dehydrogenase (BDH2). In breast tumor biopsies from women diagnosed with BrCA we found that BDH2 expression was positively associated with adiposity and circulating Lcn2 levels. Collectively these data suggest that reduction of ERα expression in adipose tissue promotes adiposity and is linked with the progression and severity of BrCA via increased adipocyte-specific Lcn2 production and enhanced tumor cell Lcn2 sensitivity.
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http://dx.doi.org/10.1074/jbc.M114.606459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4342471PMC
February 2015

Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance.

Diabetes 2014 Jun 15;63(6):1881-94. Epub 2014 Jan 15.

Cellular and Molecular Metabolism Laboratory, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, AustraliaN-Gene Research Laboratories, Inc., Budapest, Hungary

Induction of heat shock protein (HSP)72 protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here, we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wild-type (WT) mice were fed either a chow or high-fat diet (HFD). Despite a similar energy intake when HSP72Tg mice were compared with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglycerol and diacylglycerol but not ceramide), and severe glucose intolerance in WT mice alone. Whole-body VO2, fatty acid oxidation, and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 coinducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications not only for type 2 diabetes but also for other disorders where mitochondrial function is compromised.
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http://dx.doi.org/10.2337/db13-0967DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4030108PMC
June 2014
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