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1.  Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis 
The Journal of Clinical Investigation  null;126(9):3433-3446.
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.
doi:10.1172/JCI86522
PMCID: PMC5004956  PMID: 27525440
2.  Role of PKCδ in Insulin Sensitivity and Skeletal Muscle Metabolism 
Diabetes  2015;64(12):4023-4032.
Protein kinase C (PKC)δ has been shown to be increased in liver in obesity and plays an important role in the development of hepatic insulin resistance in both mice and humans. In the current study, we explored the role of PKCδ in skeletal muscle in the control of insulin sensitivity and glucose metabolism by generating mice in which PKCδ was deleted specifically in muscle using Cre-lox recombination. Deletion of PKCδ in muscle improved insulin signaling in young mice, especially at low insulin doses; however, this did not change glucose tolerance or insulin tolerance tests done with pharmacological levels of insulin. Likewise, in young mice, muscle-specific deletion of PKCδ did not rescue high-fat diet–induced insulin resistance or glucose intolerance. However, with an increase in age, PKCδ levels in muscle increased, and by 6 to 7 months of age, muscle-specific deletion of PKCδ improved whole-body insulin sensitivity and muscle insulin resistance and by 15 months of age improved the age-related decline in whole-body glucose tolerance. At 15 months of age, M-PKCδKO mice also exhibited decreased metabolic rate and lower levels of some proteins of the OXPHOS complex suggesting a role for PKCδ in the regulation of mitochondrial mass at older age. These data indicate an important role of PKCδ in the regulation of insulin sensitivity and mitochondrial homeostasis in skeletal muscle with aging.
doi:10.2337/db14-1891
PMCID: PMC4657586  PMID: 26307588
3.  PI3-kinase mutation linked to insulin and growth factor resistance in vivo 
The Journal of Clinical Investigation  null;126(4):1401-1412.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway is central to the action of insulin and many growth factors. Heterozygous mutations in the gene encoding the p85α regulatory subunit of PI3K (PIK3R1) have been identified in patients with SHORT syndrome — a disorder characterized by short stature, partial lipodystrophy, and insulin resistance. Here, we evaluated whether SHORT syndrome–associated PIK3R1 mutations account for the pathophysiology that underlies the abnormalities by generating knockin mice that are heterozygous for the Pik3r1Arg649Trp mutation, which is homologous to the mutation found in the majority of affected individuals. Similar to the patients, mutant mice exhibited a reduction in body weight and length, partial lipodystrophy, and systemic insulin resistance. These derangements were associated with a reduced capacity of insulin and other growth factors to activate PI3K in liver, muscle, and fat; marked insulin resistance in liver and fat of mutation-harboring animals; and insulin resistance in vitro in cells derived from these mice. In addition, mutant mice displayed defective insulin secretion and GLP-1 action on islets in vivo and in vitro. These data demonstrate the ability of this heterozygous mutation to alter PI3K activity in vivo and the central role of PI3K in insulin/growth factor action, adipocyte function, and glucose metabolism.
doi:10.1172/JCI84005
PMCID: PMC4811129  PMID: 26974159
4.  Interactions between Gut Microbiota, Host Genetics and Diet Modulate the Predisposition to Obesity and Metabolic Syndrome 
Cell metabolism  2015;22(3):516-530.
Obesity, diabetes and metabolic syndrome result from complex interactions between genetic and environmental factors, including the gut microbiota. To dissect these interactions, we utilized three commonly-used inbred strains of mice – obesity/diabetes-prone C57Bl/6J mice, obesity/diabetes-resistant 129S1/SvImJ, from Jackson Laboratory and obesity-prone, but diabetes resistant 129S6/SvEvTac from Taconic - plus three derivative lines generated by breeding these strains in a new, common environment. Analysis of metabolic parameters and gut microbiota in all strains and their environmentally-normalized derivatives revealed strong interactions between microbiota, diet, breeding site and metabolic phenotype. Strain-dependent and strain-independent correlations were found between specific microbiota and phenotypes, some of which could be transferred to germ-free recipient animals by fecal transplantation. Environmental reprogramming of microbiota resulted in 129S6/SvEvTac becoming obesity-resistant. Thus, development of obesity/metabolic syndrome is the result of interactions between gut microbiota, host genetics and diet. In permissive genetic backgrounds, environmental reprograming of microbiota can ameliorate development of metabolic syndrome.
Graphical Abstract
doi:10.1016/j.cmet.2015.07.007
PMCID: PMC4570502  PMID: 26299453
Diabetes; hepatosteatosis; insulin resistance; microbiota; mouse genetics
5.  Interactions between host genetics and gut microbiome in diabetes and metabolic syndrome 
Molecular Metabolism  2016;5(9):795-803.
Background
Diabetes, obesity, and the metabolic syndrome are multifactorial diseases dependent on a complex interaction of host genetics, diet, and other environmental factors. Increasing evidence places gut microbiota as important modulators of the crosstalk between diet and development of obesity and metabolic dysfunction. In addition, host genetics can have important impact on the composition and function of gut microbiota. Indeed, depending on the genetic background of the host, diet and other environmental factors may produce different changes in gut microbiota, have different impacts on host metabolism, and create different interactions between the microbiome and the host.
Scope of review
In this review, we highlight how appropriate animal models can help dissect the complex interaction of host genetics with the gut microbiome and how diet can lead to different degrees of weight gain, levels of insulin resistance, and metabolic outcomes, such as diabetes, in different individuals. We also discuss the challenges of identifying specific disease-associated microbiota and the limitations of simple metrics, such as phylogenetic diversity or the ratio of Firmicutes to Bacteroidetes.
Major conclusions
Understanding these complex interactions will help in the development of novel treatments for microbiome-related metabolic diseases. This article is part of a special issue on microbiota.
doi:10.1016/j.molmet.2016.07.004
PMCID: PMC5004229  PMID: 27617202
Obesity; Metabolic syndrome; Microbiome; Microbiota; Microbial diversity; Host genetics; Environment
6.  Differential Role of Insulin/IGF-1 Receptor Signaling on Muscle Growth and Glucose Homeostasis 
Cell reports  2015;11(8):1220-1235.
Summary
Insulin and 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 receptor 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.
doi:10.1016/j.celrep.2015.04.037
PMCID: PMC4449334  PMID: 25981038
Insulin Resistance; Diabetes; Insulin Receptor; IGF-1 Receptor; Glucose transport
7.  Turning on Brown Fat and Muscle Metabolism: Hedging Your Bets 
Cell  2012;151(2):248-250.
Developmental genes are essential in the formation and function of adipose tissue and muscle. In this issue of Cell, Teperino et al. demonstrate that non-canonical Hedgehog signaling increases glucose uptake into brown fat and muscle. Modulation of developmental pathways may serve as potential targets for new treatments of diabetes and other metabolic disorders.
doi:10.1016/j.cell.2012.09.025
PMCID: PMC4828657  PMID: 23063118
8.  Tbx15 Controls Skeletal Muscle Fiber Type Determination and Muscle Metabolism 
Nature communications  2015;6:8054.
Skeletal muscle is composed of both slow-twich 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 fibers, associated with a small increase in the number of oxidative fibers. This shift in fiber 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 signaling 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 fiber identity and muscle metabolism.
doi:10.1038/ncomms9054
PMCID: PMC4552045  PMID: 26299309
10.  Genetic Insulin Resistance Is a Potent Regulator of Gene Expression and Proliferation in Human iPS Cells 
Diabetes  2014;63(12):4130-4142.
Insulin resistance is central to diabetes and metabolic syndrome. To define the consequences of genetic insulin resistance distinct from those secondary to cellular differentiation or in vivo regulation, we generated induced pluripotent stem cells (iPSCs) from individuals with insulin receptor mutations and age-appropriate control subjects and studied insulin signaling and gene expression compared with the fibroblasts from which they were derived. iPSCs from patients with genetic insulin resistance exhibited altered insulin signaling, paralleling that seen in the original fibroblasts. Insulin-stimulated expression of immediate early genes and proliferation were also potently reduced in insulin resistant iPSCs. Global gene expression analysis revealed marked differences in both insulin-resistant iPSCs and corresponding fibroblasts compared with control iPSCs and fibroblasts. Patterns of gene expression in patients with genetic insulin resistance were particularly distinct in the two cell types, indicating dependence on not only receptor activity but also the cellular context of the mutant insulin receptor. Thus, iPSCs provide a novel approach to define effects of genetically determined insulin resistance. This study demonstrates that effects of insulin resistance on gene expression are modified by cellular context and differentiation state. Moreover, altered insulin receptor signaling and insulin resistance can modify proliferation and function of pluripotent stem cell populations.
doi:10.2337/db14-0109
PMCID: PMC4238001  PMID: 25059784
11.  Insulin Action in Brain Regulates Systemic Metabolism and Brain Function 
Diabetes  2014;63(7):2232-2243.
Insulin receptors, as well as IGF-1 receptors and their postreceptor signaling partners, are distributed throughout the brain. Insulin acts on these receptors to modulate peripheral metabolism, including regulation of appetite, reproductive function, body temperature, white fat mass, hepatic glucose output, and response to hypoglycemia. Insulin signaling also modulates neurotransmitter channel activity, brain cholesterol synthesis, and mitochondrial function. Disruption of insulin action in the brain leads to impairment of neuronal function and synaptogenesis. In addition, insulin signaling modulates phosphorylation of tau protein, an early component in the development of Alzheimer disease. Thus, alterations in insulin action in the brain can contribute to metabolic syndrome, and the development of mood disorders and neurodegenerative diseases.
doi:10.2337/db14-0568
PMCID: PMC4066341  PMID: 24931034
12.  Adipose Depots Possess Unique Developmental Gene Signatures 
Obesity (Silver Spring, Md.)  2010;18(5):872-878.
We have previously demonstrated that subcutaneous and intra-abdominal adipose tissue show different patterns of expression for developmental genes (Shox2, En1, Tbx15 Hoxa5, Hoxc8, and Hoxc9), and that the expression level of Tbx15 and Hoxa5 in humans correlated with the level of obesity and fat distribution. To further explore the role of these developmental genes in adipose tissue, we have characterized their expression in different adipose depots in mice, and studied their regulation in obesity and by fasting. Developmental and adipogenic gene expression was compared in two subcutaneous and three intra-abdominal white adipose tissue (WAT) depots as well as brown adipose tissue (BAT) from lean or obese mice in a fed or fasting state. Each of these six adipose depots display a unique pattern of developmental gene expression, whereas expression of adipogenic transcription factors PPARγ2 C/EBPα, β, and δ showed constant expression levels in all depots. Expression levels of developmental genes were similar in obese (ob/ob and high-fat diet (HFD)) and lean mice in most depots. Fasting systematically decreased expression of Hoxc8, PPARγ2, and increased C/EBPδ in both lean and ob/ob mice, but produced only variable changes in the expression of other developmental and adipogenic genes. These data indicate that each fat depot has a unique developmental gene expression signature, which is largely independent of nutritional state. This finding further supports a fundamental role of developmental genes in fat distribution and the development and/or function of specific adipose tissue depots.
doi:10.1038/oby.2009.512
PMCID: PMC4377838  PMID: 20111017
13.  Receptor Antibodies and Novel Ligands as Potential Therapeutics for Diabetes 
Science translational medicine  2011;3(113):113ps47.
Summary
Antibodies to receptors can block or mimic hormone action. Taking advantage of receptor isoforms, co-receptors and other receptor modulating proteins, antibodies and other designer ligands can enhance tissue specificity and provide new approaches to the therapy of diabetes and other diseases.
doi:10.1126/scitranslmed.3003447
PMCID: PMC4374142  PMID: 22174312
Anti-receptor antibodies; FGF21; insulin receptor; co-receptors; receptor isoforms; brown adipose tissue
14.  Evaluation of the Unfolded Protein Response: PI 3-Kinase Regulatory Subunits as Regulators of the IRE1α Pathway 
Methods in enzymology  2011;490:147-158.
The endoplasmic reticulum (ER) consists of an interconnected, membranous network that is the major site for the synthesis and folding of integral membrane and secretory proteins. Within the ER lumen, protein folding is facilitated by molecular chaperones and a variety of enzymes that ensure that polypeptides obtain their appropriate, tertiary conformation (1,2). Physiological conditions that increase protein synthesis or stimuli that disturb the processes by which proteins obtain their native conformation, create an imbalance between the protein-folding demand and capacity of the ER. This results in the accumulation of unfolded or improperly folded proteins in the ER lumen and a state of ER stress. The cellular response, referred to as the unfolded protein response (UPR), results in activation of three linked signal transduction pathways: PKR-like kinase (PERK), inositol requiring 1 α (IRE1α) and activating transcription factor 6α (ATF6α) (3,4). Collectively, the combined actions of these signaling cascades serve to reduce ER stress through attenuation of translation to reduce protein synthesis and through activation of transcriptional programs that ultimately serve to increase ER protein folding capacity. Recently, we and Park et. al have characterized a novel function for the p85α and p85β subunits as modulators of the UPR by virtue of their ability to facilitate the nuclear entry of XBP-1s following induction of ER stress (5,6). This chapter describes the recently elucidated role for the regulatory subunits of PI 3-kinase as modulators of the UPR and provides methods to measure UPR pathway activation.
doi:10.1016/B978-0-12-385114-7.00009-X
PMCID: PMC4371597  PMID: 21266249
15.  A Novel Interaction Between the Regulatory Subunit of PI 3-Kinase and X-box Binding Protein-1 Modulates the Unfolded Protein Response 
Nature medicine  2010;16(4):438-445.
Class Ia phosphoinositide (PI) 3-kinase, an essential mediator of the metabolic actions of insulin, is composed of a catalytic (p110α) and regulatory (p85α) subunit. Here we demonstrate that p85α interacts with X-box binding protein-1 (XBP-1), a transcriptional mediator of the unfolded protein response (UPR), in an ER stress-dependent manner. Cell lines with knockout or knockdown of p85α exhibit dramatic alterations in the UPR including reduced ER stress-dependent accumulation of nuclear XBP-1, decreased induction of UPR target genes and increased rates of apoptosis. This is associated with a decrease activation of IRE1α and ATF6α. Mice with deletion of p85α in liver (L-Pik3r1−/−) display a similar attenuated UPR following tunicamycin administration leading to an increased inflammatory response. Thus, p85α forms a novel link between the PI 3-kinase pathway, which is central to insulin action, and the regulation of the cellular response to ER stress, which can lead to insulin resistance.
doi:10.1038/nm.2121
PMCID: PMC4371606  PMID: 20348923
16.  A Kinase-Independent Role for Unoccupied Insulin and IGF-1 Receptors in the Control of Apoptosis 
Science signaling  2010;3(151):ra87.
Insulin and insulin-like growth factor 1 (IGF-1) act as anti-apoptotic hormones. We found that, unexpectedly, double knockout (DKO) cells that lacked both insulin and IGF-1 receptors (IR and IGF1R, respectively), were resistant to apoptosis induced through either the intrinsic or extrinsic pathway. This resistance to apoptosis was associated with decreased abundance of the pro-apoptotic protein Bax and increases in abundance of the anti-apoptotic proteins Bcl-2, Bcl-xL, XIAP, and Flip. These changes in protein abundance involved primarily post-transcriptional mechanisms. Restoration of the insulin or IGF-1 receptor to DKO cells also restored their sensitivity to apoptosis. Notably, expression of a catalytically inactive mutant form of the insulin receptor also restored susceptibility to apoptosis. Thus, the insulin and IGF-1 receptors have bidirectional roles in the control of cell survival and can be viewed as previously-unidentified dependence receptors. Insulin and IGF-1 binding stimulates receptor tyrosine kinase activity and blocks apoptosis, whereas unliganded insulin and IGF-1 receptors, acting through a mechanism independent of their catalytic activity, exert a permissive effect on cell death.
doi:10.1126/scisignal.2001173
PMCID: PMC4364396  PMID: 21139139
Insulin receptor; IGF-1 receptor; Brown adipose tissue; Apoptosis; Bax; Bcl-2; Flip; Caspases; Dependence receptors
17.  Transplantation of Adipose Tissue and Adipose-Derived Stem Cells as a Tool to Study Metabolic Physiology and for Treatment of Disease 
Nature reviews. Endocrinology  2010;6(4):195-213.
Humans and other mammals have three main fat depots - visceral white fat, subcutaneous white fat, and brown fat - each possessing unique cell-autonomous properties. In contrast to visceral fat which can induce detrimental metabolic effects, subcutaneous white fat and brown fat have potential beneficial metabolic effects, including improved glucose homeostasis and increased energy consumption, which might be transferred by transplantation of these fat tissues. In addition, fat contains adipose-derived stem cells that have been shown to have multilineage properties which may be of value in repair or replacement of various cell lineages. Thus, transplantation of fat is now being explored as a possible tool to capture the beneficial metabolic effects of subcutaneous white fat, brown fat, and adipose-derived stem cells. Currently, fat transplantation has been explored primarily as a tool to study physiology, with the only application to humans being reconstructive surgery. Ultimately, the application of fat transplantation for treatment of obesity and metabolic disorders will reside in the level of safety, reliability, and efficacy when compared to other treatments.
doi:10.1038/nrendo.2010.20
PMCID: PMC4362513  PMID: 20195269
18.  The Origin of Fat: Can We Nip Obesity in the Vascular Bud? 
Science (New York, N.Y.)  2008;322(5901):542-543.
doi:10.1126/science.1165667
PMCID: PMC4351775  PMID: 18948531
19.  Insulin Receptor Signaling in Normal and Insulin-Resistant States 
In the wake of the worldwide increase in type-2 diabetes, a major focus of research is understanding the signaling pathways impacting this disease. Insulin signaling regulates glucose, lipid, and energy homeostasis, predominantly via action on liver, skeletal muscle, and adipose tissue. Precise modulation of this pathway is vital for adaption as the individual moves from the fed to the fasted state. The positive and negative modulators acting on different steps of the signaling pathway, as well as the diversity of protein isoform interaction, ensure a proper and coordinated biological response to insulin in different tissues. Whereas genetic mutations are causes of rare and severe insulin resistance, obesity can lead to insulin resistance through a variety of mechanisms. Understanding these pathways is essential for development of new drugs to treat diabetes, metabolic syndrome, and their complications.
Insulin and IGF-1 act via tyrosine kinase receptors to produce signals that control biological processes. The signaling pathways are precisely regulated, and perturbations in them may lead to insulin resistance.
doi:10.1101/cshperspect.a009191
PMCID: PMC3941218  PMID: 24384568
20.  Insulin Signaling to the Glomerular Podocyte is Critical for Normal Kidney Function 
Cell metabolism  2010;12(4):329-340.
Summary
Diabetic nephropathy (DN) is the leading cause of renal failure in the world. It is characterized by albuminuria and abnormal glomerular function and is considered a hyperglycaemic “microvascular’ complication of diabetes, implying a primary defect in the endothelium. However, we have previously shown that human podocytes have robust responses to insulin. To determine whether insulin signaling in podocytes affects glomerular function in vivo we generated mice with specific deletion of the insulin receptor from their podocytes. These animals develop significant albuminuria together with histological features that recapitulate DN, but in a normoglycaemic environment. Examination of “normal” insulin responsive podocytes in vivo and in vitro demonstrates that insulin signals through the MAPK and PI3-kinase pathways via the insulin receptor and directly remodels the actin cytoskeleton of this cell. Collectively, this work reveals the critical importance of podocyte insulin sensitivity for kidney function.
Graphical abstract
doi:10.1016/j.cmet.2010.08.015
PMCID: PMC4949331  PMID: 20889126
21.  Differential effects of angiopoietin-like 4 in brain and muscle on regulation of lipoprotein lipase activity 
Molecular Metabolism  2014;4(2):144-150.
Objective
Lipoprotein lipase (LPL) is a key regulator of circulating triglyceride rich lipoprotein hydrolysis. In brain LPL regulates appetite and energy expenditure. Angiopoietin-like 4 (Angptl4) is a secreted protein that inhibits LPL activity and, thereby, triglyceride metabolism, but the impact of Angptl4 on central lipid metabolism is unknown.
Methods
We induced type 1 diabetes by streptozotocin (STZ) in whole-body Angptl4 knockout mice (Angptl4-/-) and their wildtype littermates to study the role of Angptl4 in central lipid metabolism.
Results
In type 1 (streptozotocin, STZ) and type 2 (ob/ob) diabetic mice, there is a ~2-fold increase of Angptl4 in the hypothalamus and skeletal muscle. Intracerebroventricular insulin injection into STZ mice at levels which have no effect on plasma glucose restores Angptl4 expression in hypothalamus. Isolation of cells from the brain reveals that Angptl4 is produced in glia, whereas LPL is present in both glia and neurons. Consistent with the in vivo experiment, in vitro insulin treatment of glial cells causes a 50% reduction of Angptl4 and significantly increases LPL activity with no change in LPL expression. In Angptl4-/- mice, LPL activity in skeletal muscle is increased 3-fold, and this is further increased by STZ-induced diabetes. By contrast, Angptl4-/- mice show no significant difference in LPL activity in hypothalamus or brain independent of diabetic and nutritional status.
Conclusion
Thus, Angptl4 in brain is produced in glia and regulated by insulin. However, in contrast to the periphery, central Angptl4 does not regulate LPL activity, but appears to participate in the metabolic crosstalk between glia and neurons.
doi:10.1016/j.molmet.2014.11.003
PMCID: PMC4314546  PMID: 25685701
Angptl4; Lipid metabolism; Lipoprotein lipase; AgRP, agouti-related protein; Angptl4, angiopoietin-like 4; ARC, arcuate nucleus; CART, cocaine-and-amphetamine-regulated transcript; CNS, central nervous system; FFA, free fatty acid; LPL, lipoprotein lipase; NPY, neuropeptide-Y; POMC, pro-opiomelanocortin; STZ, streptozotocin; TG, triglyceride
22.  Sirt3 Regulates Metabolic Flexibility of Skeletal Muscle Through Reversible Enzymatic Deacetylation 
Diabetes  2013;62(10):3404-3417.
Sirt3 is an NAD+-dependent deacetylase that regulates mitochondrial function by targeting metabolic enzymes and proteins. In fasting mice, Sirt3 expression is decreased in skeletal muscle resulting in increased mitochondrial protein acetylation. Deletion of Sirt3 led to impaired glucose oxidation in muscle, which was associated with decreased pyruvate dehydrogenase (PDH) activity, accumulation of pyruvate and lactate metabolites, and an inability of insulin to suppress fatty acid oxidation. Antibody-based acetyl-peptide enrichment and mass spectrometry of mitochondrial lysates from WT and Sirt3 KO skeletal muscle revealed that a major target of Sirt3 deacetylation is the E1α subunit of PDH (PDH E1α). Sirt3 knockout in vivo and Sirt3 knockdown in myoblasts in vitro induced hyperacetylation of the PDH E1α subunit, altering its phosphorylation leading to suppressed PDH enzymatic activity. The inhibition of PDH activity resulting from reduced levels of Sirt3 induces a switch of skeletal muscle substrate utilization from carbohydrate oxidation toward lactate production and fatty acid utilization even in the fed state, contributing to a loss of metabolic flexibility. Thus, Sirt3 plays an important role in skeletal muscle mitochondrial substrate choice and metabolic flexibility in part by regulating PDH function through deacetylation.
doi:10.2337/db12-1650
PMCID: PMC3781465  PMID: 23835326
23.  Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy 
The Journal of Clinical Investigation  2014;124(8):3339-3351.
miRNAs are important regulators of biological processes in many tissues, including the differentiation and function of brown and white adipocytes. The endoribonuclease dicer is a major component of the miRNA-processing pathway, and in adipose tissue, levels of dicer have been shown to decrease with age, increase with caloric restriction, and influence stress resistance. Here, we demonstrated that mice with a fat-specific KO of dicer develop a form of lipodystrophy that is characterized by loss of intra-abdominal and subcutaneous white fat, severe insulin resistance, and enlargement and “whitening” of interscapular brown fat. Additionally, KO of dicer in cultured brown preadipocytes promoted a white adipocyte–like phenotype and reduced expression of several miRNAs. Brown preadipocyte whitening was partially reversed by expression of miR-365, a miRNA known to promote brown fat differentiation; however, introduction of other miRNAs, including miR-346 and miR-362, also contributed to reversal of the loss of the dicer phenotype. Interestingly, fat samples from patients with HIV-related lipodystrophy exhibited a substantial downregulation of dicer mRNA expression. Together, these findings indicate the importance of miRNA processing in white and brown adipose tissue determination and provide a potential link between this process and HIV-related lipodystrophy.
doi:10.1172/JCI73468
PMCID: PMC4109560  PMID: 24983316
24.  Tbx15 controls skeletal muscle fibre-type determination and muscle metabolism 
Nature Communications  2015;6:8054.
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.
The transcriptional regulator Tbx15 has a role in organ development. Here Lee et al. show that Tbx15 influences fibre-type determination in murine skeletal muscles, explaining local and systemic metabolic derangements in heterozygous Tbx15 knockout mice.
doi:10.1038/ncomms9054
PMCID: PMC4552045  PMID: 26299309
25.  Complex mechanisms linking neurocognitive dysfunction to insulin resistance and other metabolic dysfunction 
F1000Research  2016;5:353.
Scientific evidence has established several links between metabolic and neurocognitive dysfunction, and epidemiologic evidence has revealed an increased risk of Alzheimer’s disease and vascular dementia in patients with diabetes. In July 2015, the National Institute of Diabetes, Digestive, and Kidney Diseases gathered experts from multiple clinical and scientific disciplines, in a workshop entitled “The Intersection of Metabolic and Neurocognitive Dysfunction”, to clarify the state-of-the-science on the mechanisms linking metabolic dysfunction, and insulin resistance and diabetes in particular, to neurocognitive impairment and dementia. This perspective is intended to serve as a summary of the opinions expressed at this meeting, which focused on identifying gaps and opportunities to advance research in this emerging area with important public health relevance.
doi:10.12688/f1000research.8300.2
PMCID: PMC4897751  PMID: 27303627
Diabetes; insulin resistance; obesity; cognition; cognitive impairment; Alzheimer’s disease; vascular dementia; mechanism

Results 1-25 (153)