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One or more keywords matched the following properties of Kim, Jason
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keywords Insulin Resistance
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Metabolic and Molecular Research in Obesity, Type 2 Diabetes, and Diabetic Heart Disease

My research for almost 30 years has focused on obesity, insulin resistance, and type 2 diabetes, and I have made a significant contribution to the field with 166 peer-reviewed publications, mostly in high-impact scientific journals, such as Nature, Science, and Cell Metabolism. Insulin resistance is a major cause of type 2 diabetes, and my research program has largely explored the molecular link between inflammation and insulin resistance using transgenic mice with elegant in vivo metabolic experiments and molecular approaches. Heart disease is a leading cause of death for people with diabetes, and my research also investigates the role of inflammation and altered myocardial metabolism in diabetic cardiomyopathy. As a leading expert on mouse metabolism and diabetes research and as Program Director of NIH-funded National Mouse Metabolic Phenotyping Center at UMass (https://www.mmpc.org/), my group has also studied more than 400 genetic mouse models of human diseases and collaborated with academic and industry investigators worldwide in joint efforts to understand the etiology of type 2 diabetes and its complications and to identify potential therapeutic targets. Overall, my research projects are highly translational in their abilities to better understand the etiology and pathogenesis of type 2 diabetes and its complications in humans.

Project 1: Role of GRP78 and Unfolded Protein Response in Macrophage Function and Insulin Resistance in Diet-Induced Obesity

We have recently found that obesity-mediated inflammation is associated with M1 polarization of macrophages and increased secretion of inflammatory cytokines and their deleterious effects on skeletal muscle insulin signaling and glucose metabolism. The 78-kDa glucose-regulated protein (GRP78) is a major endoplasmic reticulum (ER) chaperone, and our recently published work showed that GRP78 modulates unfolded protein response (UPR) and ER homeostasis. Based on these findings, we have recently generated mice with conditional deletion of Grp78 in myeloid cells (Lyz-Grp78-/-), and Lyz-Grp78-/- mice are shown to be protected from obesity-mediated insulin resistance, and the underlying mechanism involves upregulation of ATF-4 and other UPR elements with increased alternatively-activated (M2) macrophages, resulting in increased insulin signaling and glucose metabolism in skeletal muscle. Our findings implicate a potential role of ER stress and UPR in macrophage function, and we are continuing to investigate the effects of obesity in macrophages and other immune cells.

Project 2: Role of IFNg and IL-1a in Obesity-Mediated Inflammation and Insulin Resistance

Interferon-g (IFNg) and IL-1a are major inflammatory cytokines elevated in obesity, but their role in obesity-mediated insulin resistance and type 2 diabetes is unknown. As a primary modulator of the macrophage phenotype, IFNg promotes a strong pro-inflammatory M1 macrophage response that correlates with macrophage recruitment to metabolic organs in obesity. We have recently generated mice with conditional deletion of IFNg receptor (Lyz-IFNgR2 KO) to disrupt the IFNg signaling in myeloid cells, and we are currently investigating the effects of diet-induced obesity in Lyz-IFNgR2 KO mice. We have also generated mice with conditional deletion of IL-1a in myeloid cells (Lyz-IL1a KO) to determine the effects of myeloid cells lacking IL-1a in obesity-mediated inflammation and insulin resistance.

Project 3: Role of Altered Gut Microbiome in Obesity and Type 2 Diabetes

The gut microbiota and their secreted metabolites have profound effects on host energy balance and metabolism. Although recent studies have shown altered gut microbial communities in obese and diabetic humans and animals, their role in the pathogenesis of metabolic diseases remains unclear. We have recently found that antibiotic-mediated alteration in gut microbiota affects energy balance and obesity during chronic high-fat feeding, and these effects are differentially regulated in male and female mice. Using antibiotics, fecal microbiota transplant, and ovariectomy, we are investigating the underlying mechanism of gender-selective effects of altered gut microbiota on energy homeostasis and metabolism.

Project 4: Role of ER Stress and Inflammation in Myocardial Metabolism and Diabetic Heart Disease

We were the first to demonstrate that diet-induced obesity causes myocardial inflammation and affects key metabolic signaling processes, suggesting a possible role of inflammation in diabetic heart disease. We have also found that diet-induced obesity causes insulin resistance in the heart with defects in myocardial insulin signaling and glucose metabolism. Based on these findings, we have recently generated mice with heart-selective deletion of the c-Jun kinase (JNK), GRP78, and uncoupling protein (UCP) to determine the role of excess lipid oxidation and ER stress in myocardial inflammation and insulin resistance in obesity. Using these cardiac mouse models and in vivo imaging system to assess cardiac function and structure, we are continuing to identify new molecular pathways by which obesity affects myocardial metabolism and causes diabetic heart disease.

Project 5: Role of Anti-Inflammatory Cytokine, IL-10 in Regulation of Glucose Metabolism, Insulin Signaling, and Skeletal Muscle Myogenesis

We have initially made two important discoveries: 1) In diet-induced obesity, inflammation develops in skeletal muscle with macrophage infiltration and locally elevated inflammatory cytokines, and 2) cytokines regulate glucose metabolism and insulin signaling in skeletal muscle. Based on these findings, we have generated transgenic mice with muscle-selective overexpression of IL-10 (MIL-10), and MIL-10 mice are protected from obesity-mediated inflammation and insulin resistance in skeletal muscle. We have also found that MIL-10 mice remain more insulin sensitive with increased glucose metabolism in aging, suggesting a potential role of muscle inflammation in aging-associated insulin resistance. Interestingly, we have found increased muscle mass in MIL-10 mice, and we are continuing to investigate the molecular mechanisms by which IL-10 regulates muscle inflammation, insulin signaling, and myogenesis and identify potential therapeutic targets for the treatment of insulin resistance (pre-diabetes) in obesity and aging.

Summary My research for almost 30 years has focused on obesity, insulin resistance, and type 2 diabetes and explores the molecular link between inflammation and insulin resistance using transgenic mice with elegant in vivo metabolic experiments and molecular approaches. My research also investigates the role of inflammation and altered metabolism in diabetic heart disease.
One or more keywords matched the following items that are connected to Kim, Jason
Item TypeName
Academic Article Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle.
Academic Article Differential effects of rosiglitazone on skeletal muscle and liver insulin resistance in A-ZIP/F-1 fatless mice.
Academic Article Genetic modulation of PPARgamma phosphorylation regulates insulin sensitivity.
Academic Article Differential effects of interleukin-6 and -10 on skeletal muscle and liver insulin action in vivo.
Academic Article Comparing adiposity profiles in three mouse models with altered GH signaling.
Academic Article Hypertension and abnormal fat distribution but not insulin resistance in mice with P465L PPARgamma.
Academic Article PKC-theta knockout mice are protected from fat-induced insulin resistance.
Academic Article Adipocyte-specific overexpression of FOXC2 prevents diet-induced increases in intramuscular fatty acyl CoA and insulin resistance.
Academic Article Effects of chronic Akt activation on glucose uptake in the heart.
Academic Article The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis.
Academic Article Mechanism of glucose intolerance in mice with dominant negative mutation of CEACAM1.
Academic Article Loss of the Par-1b/MARK2 polarity kinase leads to increased metabolic rate, decreased adiposity, and insulin hypersensitivity in vivo.
Academic Article Overexpression of uncoupling protein 3 in skeletal muscle protects against fat-induced insulin resistance.
Academic Article Hyperglycemia, maturity-onset obesity, and insulin resistance in NONcNZO10/LtJ males, a new mouse model of type 2 diabetes.
Academic Article The proinflammatory cytokine macrophage migration inhibitory factor regulates glucose metabolism during systemic inflammation.
Academic Article A stress signaling pathway in adipose tissue regulates hepatic insulin resistance.
Academic Article COMP-angiopoietin-1 enhances skeletal muscle blood flow and insulin sensitivity in mice.
Academic Article Hyperinsulinemic-euglycemic clamp to assess insulin sensitivity in vivo.
Academic Article The transcription factor ATF4 regulates glucose metabolism in mice through its expression in osteoblasts.
Academic Article An Osteoblast-dependent mechanism contributes to the leptin regulation of insulin secretion.
Academic Article Role of muscle c-Jun NH2-terminal kinase 1 in obesity-induced insulin resistance.
Academic Article FoxO1 expression in osteoblasts regulates glucose homeostasis through regulation of osteocalcin in mice.
Academic Article Role of the hypothalamic-pituitary-thyroid axis in metabolic regulation by JNK1.
Academic Article Fat cell-specific ablation of rictor in mice impairs insulin-regulated fat cell and whole-body glucose and lipid metabolism.
Academic Article Carcinoembryonic antigen-related cell adhesion molecule 2 controls energy balance and peripheral insulin action in mice.
Academic Article Early hepatic insulin resistance precedes the onset of diabetes in obese C57BLKS-db/db mice.
Academic Article Increased hepatic insulin action in diet-induced obese mice following inhibition of glucosylceramide synthase.
Academic Article PKCzeta-regulated inflammation in the nonhematopoietic compartment is critical for obesity-induced glucose intolerance.
Academic Article Requirement of JIP1-mediated c-Jun N-terminal kinase activation for obesity-induced insulin resistance.
Academic Article Requirement of the ATM/p53 tumor suppressor pathway for glucose homeostasis.
Academic Article The association of phosphoinositide 3-kinase enhancer A with hepatic insulin receptor enhances its kinase activity.
Academic Article Essential role of protein tyrosine phosphatase 1B in obesity-induced inflammation and peripheral insulin resistance during aging.
Academic Article Cytoplasmic polyadenylation element binding protein deficiency stimulates PTEN and Stat3 mRNA translation and induces hepatic insulin resistance.
Academic Article Adrenalectomy improves diabetes in A-ZIP/F-1 lipoatrophic mice by increasing both liver and muscle insulin sensitivity.
Academic Article CD40 deficiency in mice exacerbates obesity-induced adipose tissue inflammation, hepatic steatosis, and insulin resistance.
Academic Article Baf60c drives glycolytic metabolism in the muscle and improves systemic glucose homeostasis through Deptor-mediated Akt activation.
Academic Article Role of the mixed-lineage protein kinase pathway in the metabolic stress response to obesity.
Academic Article Insulin resistance in tetracycline-repressible Munc18c transgenic mice.
Academic Article Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle.
Academic Article Transgenic overexpression of protein-tyrosine phosphatase 1B in muscle causes insulin resistance, but overexpression with leukocyte antigen-related phosphatase does not additively impair insulin action.
Academic Article Nonacute effects of H-FABP deficiency on skeletal muscle glucose uptake in vitro.
Academic Article Syntaxin 4 transgenic mice exhibit enhanced insulin-mediated glucose uptake in skeletal muscle.
Academic Article Caveolin-3 knockout mice show increased adiposity and whole body insulin resistance, with ligand-induced insulin receptor instability in skeletal muscle.
Academic Article Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart.
Academic Article Role of Rho-kinase in regulation of insulin action and glucose homeostasis.
Academic Article Cardiac-specific overexpression of peroxisome proliferator-activated receptor-alpha causes insulin resistance in heart and liver.
Academic Article Unraveling the temporal pattern of diet-induced insulin resistance in individual organs and cardiac dysfunction in C57BL/6 mice.
Academic Article Mice lacking MAP kinase phosphatase-1 have enhanced MAP kinase activity and resistance to diet-induced obesity.
Academic Article Fat uses a TOLL-road to connect inflammation and diabetes.
Academic Article Endocrine regulation of energy metabolism by the skeleton.
Academic Article Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B.
Academic Article Nonobese, insulin-deficient Ins2Akita mice develop type 2 diabetes phenotypes including insulin resistance and cardiac remodeling.
Academic Article Comparison between surrogate indexes of insulin sensitivity and resistance and hyperinsulinemic euglycemic clamp estimates in mice.
Academic Article Txnip balances metabolic and growth signaling via PTEN disulfide reduction.
Academic Article Carcinoembryonic antigen-related cell adhesion molecule 1: a link between insulin and lipid metabolism.
Academic Article Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice.
Academic Article Skeletal muscle-specific deletion of lipoprotein lipase enhances insulin signaling in skeletal muscle but causes insulin resistance in liver and other tissues.
Academic Article Liver-specific deletion of protein-tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet-induced endoplasmic reticulum stress.
Academic Article The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity.
Academic Article Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle.
Academic Article Grp78 heterozygosity promotes adaptive unfolded protein response and attenuates diet-induced obesity and insulin resistance.
Academic Article KSR2 is an essential regulator of AMP kinase, energy expenditure, and insulin sensitivity.
Academic Article Prevention of steatosis by hepatic JNK1.
Academic Article Uncoupling of inflammation and insulin resistance by NF-kappaB in transgenic mice through elevated energy expenditure.
Academic Article Deficiency of phosphoinositide 3-kinase enhancer protects mice from diet-induced obesity and insulin resistance.
Academic Article Inflammation and insulin resistance: an old story with new ideas.
Academic Article Circulating sphingolipid biomarkers in models of type 1 diabetes.
Academic Article Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans.
Academic Article New insights into insulin resistance in the diabetic heart.
Academic Article TRPM2 Ca2+ channel regulates energy balance and glucose metabolism.
Academic Article Endothelial nuclear factor ?B in obesity and aging: is endothelial nuclear factor ?B a master regulator of inflammation and insulin resistance?
Academic Article JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation.
Academic Article Short-term weight loss attenuates local tissue inflammation and improves insulin sensitivity without affecting adipose inflammation in obese mice.
Concept Insulin
Concept Insulin Receptor Substrate Proteins
Concept Insulin-Like Growth Factor I
Concept Insulin-Secreting Cells
Concept Receptor, Insulin
Concept Insulin Antagonists
Academic Article Cardiac expression of human type 2 iodothyronine deiodinase increases glucose metabolism and protects against doxorubicin-induced cardiac dysfunction in male mice.
Academic Article KLF15 is a molecular link between endoplasmic reticulum stress and insulin resistance.
Academic Article RAGE regulates the metabolic and inflammatory response to high-fat feeding in mice.
Academic Article The PPAR?-FGF21 hormone axis contributes to metabolic regulation by the hepatic JNK signaling pathway.
Academic Article Deficiency of the tumor promoter gene wip1 induces insulin resistance.
Academic Article A major role of insulin in promoting obesity-associated adipose tissue inflammation.
Academic Article Forced Hepatic Overexpression of CEACAM1 Curtails Diet-Induced Insulin Resistance.
Academic Article Transient receptor potential vanilloid type-1 channel regulates diet-induced obesity, insulin resistance, and leptin resistance.
Academic Article Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues.
Academic Article Increased Glucose-induced Secretion of Glucagon-like Peptide-1 in Mice Lacking the Carcinoembryonic Antigen-related Cell Adhesion Molecule 2 (CEACAM2).
Academic Article Genetic ablation of lymphocytes and cytokine signaling in nonobese diabetic mice prevents diet-induced obesity and insulin resistance.
Academic Article Tenomodulin promotes human adipocyte differentiation and beneficial visceral adipose tissue expansion.
Academic Article Altered miRNA processing disrupts brown/white adipocyte determination and associates with lipodystrophy.
Academic Article PI3-kinase mutation linked to insulin and growth factor resistance in vivo.
Academic Article Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.
Academic Article Protein Kinase Mitogen-activated Protein Kinase Kinase Kinase Kinase 4 (MAP4K4) Promotes Obesity-induced Hyperinsulinemia.
Academic Article ChREBP regulates fructose-induced glucose production independently of insulin signaling.
Academic Article Glucose Transporter-4 Facilitates Insulin-Stimulated Glucose Uptake in Osteoblasts.
Academic Article IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle.
Academic Article Altered Interleukin-10 Signaling in Skeletal Muscle Regulates Obesity-Mediated Inflammation and Insulin Resistance.
Academic Article Adipocyte-specific Hypoxia-inducible gene 2 promotes fat deposition and diet-induced insulin resistance.
Academic Article A Protein Scaffold Coordinates SRC-Mediated JNK Activation in Response to Metabolic Stress.
Academic Article Loss of Nuclear and Membrane Estrogen Receptor-? Differentially Impairs Insulin Secretion and Action in Male and Female Mice.
Academic Article Endoplasmic reticulum chaperone GRP78 regulates macrophage function and insulin resistance in diet-induced obesity.
Academic Article Myeloid-specific deletion of Zfp36 protects against insulin resistance and fatty liver in diet-induced obese mice.
Academic Article Myeloid-specific Acat1 ablation attenuates inflammatory responses in macrophages, improves insulin sensitivity, and suppresses diet-induced obesity.
Academic Article Nocturnal activation of melatonin receptor type 1 signaling modulates diurnal insulin sensitivity via regulation of PI3K activity.
Academic Article Liver-specific reconstitution of CEACAM1 reverses the metabolic abnormalities caused by its global deletion in male mice.
Academic Article Hyperinsulinemia drives hepatic insulin resistance in male mice with liver-specific Ceacam1 deletion independently of lipolysis.
Academic Article Adiposity-Independent Effects of Aging on Insulin Sensitivity and Clearance in Mice and Humans.
Academic Article Multi-dimensional Transcriptional Remodeling by Physiological Insulin In Vivo.
Academic Article GABA-stimulated adipose-derived stem cells suppress subcutaneous adipose inflammation in obesity.
Academic Article Mss51 deletion enhances muscle metabolism and glucose homeostasis in mice.
Academic Article Arrestin domain-containing 3 (Arrdc3) modulates insulin action and glucose metabolism in liver.
Academic Article Exogenous GDF11, but not GDF8, reduces body weight and improves glucose homeostasis in mice.
Academic Article Hepatic NADH reductive stress underlies common variation in metabolic traits.
Academic Article Muscle-Specific Insulin Receptor Overexpression Protects Mice From Diet-Induced Glucose Intolerance but Leads to Postreceptor Insulin Resistance.
Academic Article Characterization of viral insulins reveals white adipose tissue-specific effects in mice.
Academic Article Disrupted glucose homeostasis and skeletal-muscle-specific glucose uptake in an exocyst knockout mouse model.
Academic Article Maternal exposure to high-fat diet during pregnancy and lactation predisposes normal weight offspring mice to develop hepatic inflammation and insulin resistance.
Academic Article Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus, Hippocampus, and Nucleus Accumbens.
Academic Article Differential roles of FOXO transcription factors on insulin action in brown and white adipose tissue.
Academic Article Insulin Sensitivity Is Retained in Mice with Endothelial Loss of Carcinoembryonic Antigen Cell Adhesion Molecule 1.
Academic Article Beta-cell specific Insr deletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance.
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